Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists

ABSTRACT

Cyclic diamines of formula (I) or their pharmacologically acceptable acid addition salts, and their medical applications are described. These compounds inhibit the action of chemokines such as MIP-1a and/or MCP-1 on target cells, and are useful as a therapeutic drug and/or preventative drug in diseases, such as atherosclerosis, rheumatoid arthritis, and the like where blood monocytes and lymphocytes infiltrate into tissue.

This application is a national stage entry under 35 USC §371 ofPCT/US97/08577 filed May 20, 1997 which is a continuation-in-part ofapplication Ser. No. 08/858,238 filed May 19, 1997, now abandoned.

TECHNICAL FIELD

This invention relates to novel diarylalkyl cyclic diamine derivatives.

This invention also relates to chemokine receptor antagonists that maybe effective as a therapeutic agent and/or preventive agent for diseasessuch as atherosclerosis, rheumatoid arthritis, psoriasis, asthma,ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonaryfibrosis, and myocarditis, in which tissue infiltration of bloodmonocytes and lymphocytes plays a major role in the initiation,progression or maintenance of the disease.

BACKGROUND TECHNOLOGY

Chemokines are a group of inflammatory/immunomodulatory polypeptidefactors produced by lymphatic tissues and by activated macrophages andleukocytes at inflammatory sites; they have a molecular weight of 6-15kD, contain four cysteine residues, are basic and have heparin bindingactivity. The chemokines can be classified into two subfamilies, the CXCchemokines and CC chemokines, by the common location of the fourcysteine residues and by the differences in the chromosomal locations ofthe genes encoding them. For example IL-8 (abbreviation forinterleukin-8 is a CXC chemokine, while the CC chemokines includeMIP-1α/β (abbreviation for macrophage inflammatory protein-1α/β), MCP-1(abbreviation for monocyte chemotactic protein-1), and RANTES(abbreviation for regulated on activation, normal T-cell expressed andsecreted cytokine). There also exists a chemokine called lymphotactin,which does not fall into either chemokine subfamily. These chemokinespromote cell migration, increase the expression of cellular adhesionmolecules such as integrins, and promote cellular adhesion, and arethought to be the protein factors intimately involved in the adhesionand infiltration of leukocytes into the pathogenic sites in such asinflammatory tissues (for references, see for example, Michiel, D.,Biotechnology, 1993, 11, 739; Oppenheim, J. J., et al., Annual Review ofImmuology, 1991, 9, 617-648; Schall, T. J., Cytokine, 1991, 3, 165-183;Springer, T. A., Cell, 1994, 76, 301-314; Furie, M. B., American Journalof Pathology, 1995, 146, 1287-1301; Kelner, G. S., et al.; Science,1994, 266, 1395-1399).

For example, HIP-1α induces cell migration and causes a transientincrease in intracellular calcium ion concentration levels, an increasein the expression of integrins, adhesion molecules, and degranulation ofmonocytes and lymphocytes, and inhibits bone marrow stem cellproliferation (See for example, Wolpe, S. D., et al., Journal ofExperimental Medicine, 1998, 167, 570-581; Wolpe, S. D., et al., FasebJournal, 1989, 3, 2565-2573; Taub, D. D., at al., Science, 1993, 260,355-358; Schall. T. J., at al., Journal of Experimental Medicine, 1993,177, 1821-1825; Neote, K., et al., Cell, 1993, 72, 415-425; Vaddi, K.,et al., The Journal of Immunology, 1994, 153, 4721-4732).

With respect to the activity of HIP-1α in vivo and its role in thepathogenesis of disease, it has been reported that it is a pyrogen inrabbits (see for example Davatelis, G., et al., Science, 1989, 243,1066-1068); that MIP-1α injection into mouse foot pads results in aninflammatory reaction such as infiltration by neutrophils andmononuclear cells (see for example Alam, R., et al., The Journal ofImmunology, 1994, 152, 1298-1303); that MIP-1α neutralizing antibody hasan inhibitory effect or a therapeutic affect in animal models ofgranuloma, multiple sclerosis and idiopathic pulmonary fibrosis (see forexample Lukacs, N. W., et al., Journal of Experimental Medicine, 1993,177, 1551-1559; Koprus, K. J., et al., The Journal of Immunology, 1995,155, 5003-5010; Smith, R. E., et al., The Journal of Immunology, 1994,153, 4704-4712); and that coxsackie virus induced myocarditis isinhibited in mice with a disrupted MIP-1α gene (see for example Cook, D.N. et al., Science, 1995, 269, 1583-1585). These studies indicate thatMIP-1α is deeply involved in the local attraction of various subtypes ofleukocytes and the initiation, progression and maintenance of resultinginflammatory response.

MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic andactivating factor) or JE) is a chemokine produced by macrophages, smoothmuscle cells, fibroblasts, and vascular endothelial cells and causescell migration and cell adhesion of monocytes, memory T cells, andnatural killer cells, as well as mediating histamine release bybasophils (For reference, see for example, Rollins, B. J., et al., Proc.Natl. Acad. Sci. USA, 1988, 85, 3738-3742; Matsushima, K., at al.,Journal of Experimental Medicine, 1989, 169, 1485-14907; Yoshimura, T.et al., Febs Letters, 1989, 244, 487-493; Rollins, B. J. et al., Blood,1991, 78, 1112-1116; Carr, M. W., at al., Proc. Natl. Acad. Sci. USA,1994, 91, 3652-3656; Jiang, Y., et al., American Journal of Physiology,1994, 267, C1112-C1118; Allavena, P., et al., European Journal ofImmunology, 1994, 24, 3233-3236; Alam, R., et al., The Journal ofClinical Investigation, 1992, 89, 723-728).

In addition, high expression of MCP-1 has been reported in diseaseswhere accumulation of monocyte/macrophage and/or T cells is thought tobe important in the initiation or progression of diseases, such asatherosclerosis, restenosis due to endothelial injury followingangioplasty, rheumatoid arthritis, glomerulonephritis, pulmonaryfibrosis, asthma and psoriasis (for reference, see for example,Firestein, G. S. et al., Arthritis and Rheumatism, 1990, 33, 768-773;Nikolic-Peterson, D. J., et al., Kidney International, 1994, 45,enlarged ed., 45, S79-S82; Thomas, P. D., et al., American Review ofRespiratory Disease, 1987, 135, 747-760; Ross, R., Nature, 1993, 362,801-809; Cooper, K. D., et al., The Journal of InvestigativeDermatology, 1994, 102, 128-137; Sousa, A. R., et al., American Journalof Respiratory Cell And Molecular Biology, 1994). Furthermore,anti-MCP-1 antibody has been reported to inhibit delayed typehypersensitivity and hepatitis (for reference, see for example Rand, M.L., et al., American Journal of Pathology, 1996, 148, 855-864; Wada, T.,et al., Faseb Journal, 1996, 10, 1418-1425).

These data indicate that chemokines such as MIP-1α and MCP-1 attractmonocytes and lymphocytes to disease sites and mediate their activationand thus are thought to be intimately involved in the initiation,progression and maintenance of diseases deeply involving monocytes andlymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis,asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis,pulmonary fibrosis and myocarditis.

Therefore, drugs which inhibit the action of chemokines on target cellsmay be effective as a therapeutic and/or preventive drug in diseasessuch as atherosclerosis, rheumatoid arthritis, psoriasis, asthma,ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonaryfibrosis, and myocarditis.

Genes encoding receptors of specific chemokines have been cloned, and itis now known that these receptors are G protein-coupledseven-transmembrane receptors present on various leukocyte populations(for reference, see for example, Holmes, W. E., et al., Science 1991,253, 1278-1280; Murphy P. M., et al., Science, 253, 1280-1283; Neote, K.et al., Cell, 1993, 72, 415-425; Charo, I. F., et al., Proc. Natl. Acad.Sci. USA, 1994, 91, 2752-2756; Yamagami, S., et al., Biochem. Biophys.Res. Commun., 1994, 202, 1156-1162; Combadier, C., et al., The Journalof Biological Chemistry, 1995, 270, 16491-16494, Power, C. A., et al.,J. Biol. Chem., 1995, 270, 19495-19500; Samson, H., et al.,Biochemistry, 1996, 35, 3362-3367; Murphy, P. M., Annual Review ofImmunology, 1994, 12, 592-633). Therefore, compounds which inhibit thebinding of chemokines such as MIP-1α and/or MCP-1 to these receptors,that is, chemokine receptor antagonists, may be useful as drugs whichinhibit the action of chemokines such as MIP-1α and/or MCP-1 on thetarget cells, but there are no drugs known to have such effects.

Cyclic diamine derivatives containing diarylalkyl groups are known tohave muscarine receptor antagonistic activity (JP09-020758, Kokai) andmay be useful as a drug in the treatment of substance abuse disorders(WO9320821), may potentiate the effect of anti-cancer drugs by theinhibition of P-glycoproteins (JP03-101662, Kokai; EP363212), hascalcium antagonistic activity ((a) DE3831993, (b) WO9013539, (c)JP63-280081, Kokai; EP289227, (d) JP62-167762, Kokai; DE3600390), haveactivity on the central nervous system and inhibits hypermotility(WO8807528), have antiaggression, antipsychotic, antidepressant and,analgesic effect (JP57-500828, Kokai), has coronary vasodilatingactivity (JP51-098281, Kokai), has anti-lipidemia effect and promotesvascular blood flow (JP49-093379, Kokai; EP42366), have coronaryvasodilating activity and anti-reserpine activity (Aritomi, J., et al.,Yakugaku Zasshi, 1971, 91, 972-979); have anti-serotonin andanti-histamine activity (JP45-031193, Kokoku); and have central nervoussystem depressant activity (Vadodaria, D. J., et al., J. Med. Chem.,1969, 12, 860-865). However, these compounds differ from the novelcompounds of the present invention and these compounds have not beenknown to interfere with binding of chemokines to the target cells.

DISCLOSURE OF THE INVENTION

Therefore, it is an object of the present invention to discover smallmolecule drugs which inhibit the binding of chemokines such as MIP-1αand/or MCP-1 to their receptors on the target cells.

It is another object of the present invention to establish a method toinhibit the binding to the receptors on the target cells and/or effectson target cells of chemokines such as MIP-1α and/or MCP-1.

It is an additional object of the present invention to propose a methodfor the treatment of diseases for which the binding of chemokines suchas MIP-1α and/or MCP-1 to the receptor on the target cell is one of thecauses.

As a result of their intensive studies, the present inventors discoveredthat a cyclic diamine derivative having a diarylalkyl group or itspharmacologically acceptable acid adduct has an excellent activity toinhibit the binding of chemokines such as MIP-1α and/or MCP-1 and thelike to the receptor of a target cell, which has led to the completionof this invention.

That is, the present invention provides a cyclic diamine derivative orits pharmacologically acceptable acid adduct (Invention 1), representedby the formula [I] below:

[wherein R¹ and R² are identical to or different from each otherrepresenting a phenyl group or an aromatic heterocyclic group having 1-3heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogenatoms, in which the phenyl or aromatic heterocyclic group may besubstituted by any number of halogen atoms, hydroxy groups, C₁-C₈ loweralkyl groups, C₁-C₆ lower alkoxy groups, phenyl groups, benzyl groups,phenoxy groups, methylenedioxy groups, C₁-C₆ hydroxyalkyl groups,carboxy groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoylamino groups,dioxolanyl groups, or by group represented by the formula: —NR⁵R⁶, orelse may be condensed with a benzene ring to form a condensed ring,furthermore above substituents for the phenyl or aromatic heterocyclicgroup and the condensed ring condensed with a benzene ring areoptionally substituted by any substituents independently selected fromhalogen atoms, hydroxy groups, or C₁-C₆ lower alkoxy groups, and R⁵ andR⁶ may be identical to or different from each other representinghydrogen atoms, C₁-C₆ lower alkyl groups , or C₂-C₆ lower alkenylgroups;

R³ represents a hydrogen atom, hydroxy group, cyano group, C₁-C₆ loweralkoxy group or C₂-C₇ lower alkanoyloxy group;

j represents an integer of 0-3;

k represents 2 or 3;

R⁴ is a group represented by:

Formula: —A¹—R⁷  1)

(in the formula, R⁷ represents a phenyl group which may be substitutedby any number of the same or different {halogen atoms, hyroxy groups,amino groups, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups, cyanogroups, nitro groups, trifluoromethyl groups, C₂-C₇ alkoxycarbonylgroups, C₂-C₇ alkanoyl groups, C₁-C₆ alkylsulfonyl groups,trifluoromethylsulfonyl groups, phenylsulfonyl groups (which may besubstituted with a hydroxy group}, 1-pyrrolylsulfonyl groups, C₁-C₆hydroxyalkylsulfonyl groups, C₁-C₆ alkanoylamino groups, or a grouprepresented by the formula: —CONR⁸R⁹) in which R⁸ and R⁹, identical toor different from each other, represent hydrogen atoms or C₁-C₆ loweralkyl groups; A¹ is a group represented by the formula: —(CH₂)_(m)— or agroup represented by formula: —(CH₂)_(p)—G—(CH₂)_(q)— in which Grepresents G₁ or G₂; G¹ represents —O—, —CO—, —SO₂—, —CO—O—, —CONH—,—NHCO—, —NHCONH—, or —NH—SO₂—; G² represents —(C═NH)NH—SO₂—,—CO—NH—NH—CO—, —CO—NH—NH—CO—NR¹⁰—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, or—CO—N(CH₂—CO—OCH₃)—NH—CO—; R¹⁰ represents a hydrogen atom or a phenylgroup; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or1):

Formula: —A²—R¹¹  2)

(wherein A² represents —CO— or —SO₂—; R¹¹ represents:

a) A phenyl group which may be substituted by any number of the same ordifferent (halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxygroups, groups represented by formula —CH₂—NR¹²R¹³ or groups representedby the formula:

b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, andoptionally substituted with any of the same or different number of(halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups), or

c) A group represented by the formula: —CH₂—NR¹⁵R¹⁶,

where R¹², R¹³, R¹⁴ and R¹⁵, identical or different groups, representhydrogen atoms or C₁-C₆ lower alkyl groups and R¹⁶ represents (a phenylgroup or a phenylalkyl group), which may be substituted by any number ofthe same or different halogen atoms, C₁-C₆ lower alkyl group, or C₁-C₆lower alkoxy group);

Formula: —(CH₂)_(n)—R¹⁷  3)

(in the formula, R¹⁷ is a group which may be substituted at any possiblesites by any number of the same or different (halogen atoms, hydroxygroups, C₁-C₆ lower alkyl groups, or C₁-C₆ lower alkoxy group s),representing

a hydrogen atom, cyano group, C₂-C₇ alkoxycarbonyl group, C₁-C₆hydroxyalkyl group, C₁-C₆ lower alkynyl group, C₃-C₆ cycloalkyl group,C₃-C₇ alkenoyl group, a group represented by the formula:—(CHOH)CH₂OR¹⁸, a group represented by the formula: —CO—NH—NH—CO—OR¹⁹, agroup represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

in which n represents an integer of 1-4; R¹⁸ is C₁-C₆ lower alkyl group,C₂-C₆ lower alkenyl group, or C₂-C₆ lower alkynyl group and R¹⁹represents a C₁-C₆ lower alkyl group);

Formula: —(CH₂)_(r)—A³—R²⁰  4)

(wherein r represents an integer of 0-3; A³ represents a single bond,—CO—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NH—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—,—(CHOH)—CH₂—, or —(CHOH)—CH₂OCH₂—; R²⁰ represents an aromaticheterocyclic group containing 1-3 heteroatoms, selected from oxygenatoms, sulfur atoms, and/or nitrogen atoms in which the aromaticheterocyclic group may be substituted by any number of the same ordifferent (halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxygroups, or pyrrolyl groups) or may be condensed with a benzene ring toform a condensed ring); or

Formula: —CH₂—CO—NR²¹R²²  5)

(wherein R²¹ represents a hydrogen atom or C₁-C₆ lower alkyl group; R²²represents a hydrogen atom, C₁-C₆ lower alkyl group, a group representedby the formula:

a group represented by the formula:

or R²¹ and R²² may be taken together with the nitrogen to form a 4 to7-membered saturated heterocycles, which may contain an oxygen atom,sulfur atom, or another nitrogen atom; where s represents 0 or 1; trepresents an integer of 0-2; R²³ represents a hydrogen atom, hydroxygroup, phenyl group, C₁-C₆ lower alkyl group, or C₁-C₆ lower alkoxygroup; R²⁴ represents a hydrogen atom or phenyl group which may besubstituted by hydroxy group; R²⁵ represents a hydrogen atom, phenylgroup (which may be substituted by hydroxy group), C₂-C₇ alkoxycarbonylgroup, C₁-C₆ lower alkyl group, C₁-C₆ alkylthio group, or 3-indolylgroup; and R²⁶ represents a hydroxy group, amino group, C₁-C₆ loweralkoxy group, or phenylalkyloxy group);

Excepting that if R³ is a hydrogen atom, then, j is not 0, substituentfor R⁷ is not hydroxy, C₁-C₆ lower alkyl or C₁-C₆ lower alkoxy; G¹ isnot —O— or —CO—; its substituents, if R¹¹ is a phenyl group, are notC₁-C₆ lower alkyl group; R¹⁷ is not a hydrogen atom, C²-C₇alkoxycarbonyl group, or C₁-C₆ hydroxyalkyl group; r is not 0 and A³ isnot a single bond or —CO—.

Furthermore, if R³ represents a hydrogen atom and k represents 2, R⁷ isnot unsubstituted; m is not 0 and R¹¹ is not a substituted orunsubstituted phenyl group.

If R³ is a cyano group, R⁷ is not unsubstituted, and the substituentgroups for R⁷ are not halogen atom, C₁-C₆ lower alkyl group or C₁-C₆lower alkoxy group.]

The present invention provides a method of inhibiting the binding ofchemokines to the receptor of a target cell and/or a method to inhibitits action onto a target cell using a pharmacological formulationcontaining as an active ingredient, a cyclic diamine derivative or itspharmacologically acceptable acid adduct (Invention 2) represented bythe formula [II] below:

(wherein R¹ and R² are identical to or different from each otherrepresenting a phenyl group or an aromatic heterocyclic group having 1-3heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogenatoms, in which the phenyl or aromatic heterocyclic group may besubstituted by any number of halogen atoms, hydroxy groups, C₁-C₈ loweralkyl groups, C₁-C₆ lower alkoxy groups, phenyl groups, benzyl groups,phenoxy groups, methylenedioxy groups, C₁-C₆ hydroxyalkyl groups,carboxy groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoylamino groups,dioxolanyl groups, or by group represented by the formula: —NR⁵R⁶, orelse may be condensed with a benzene ring to form a condensed ring,furthermore above substituents for the phenyl or aromatic heterocyclicgroup and the condensed ring condensed with a benzene ring areoptionally substituted by any substituents independently selected fromhalogen atoms, hydroxy groups, or C₁-C₆ lower alkoxy groups, and R⁵ andR⁶ may be identical to or different from each other representinghydrogen atoms, C₁-C₆ lower alkyl groups, or C₂-C₆ lower alkenyl groups;

R³ represents a hydrogen atom, hydroxy group, cyano group, C₁-C₆ loweralkoxy group or C₂-C₇ lower alkanoyloxy group;

j represents an integer of 0-3;

k represents 2 or 3;

R⁴ is a group represented by:

Formula: —A¹—R⁷  1)

(in the formula, R⁷ represents a phenyl group which may be substitutedby any number of the same or different {halogen atoms, hydroxy groups,amino groups, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups, cyanogroups, nitro groups, trifluoromethyl groups, C₂-C₇ alkoxycarbonylgroups, C₂-C₇ alkanoyl groups, C₁-C₆ alkylsulfonyl groups,trifluoromethylsulfonyl groups, phenylsulfonyl groups (which may besubstituted with a hydroxy group}, 1-pyrrolylsulfonyl groups, C₁-C₆hydroxyalkylsulfonyl groups, C₁-C₆ alkanoylamino groups, or a grouprepresented by the formula: —CONR⁸R⁹) in which R⁸ and R⁹, identical toor different from each other, represent hydrogen atoms or C₁-C₆ loweralkyl groups; A¹ is a group represented by the formula: —(CH₂)_(m)— or agroup represented by formula: —(CH₂)_(p)—G—(CH₂)_(q)— in which Grepresents G¹ or G²; G¹ represents —O—, —CO—, —SO₂—, —CO—O—, —CONH—,—NHCO—, —NHCONH—, or —NH—SO₂—; G² represents —(C═NH)NH—SO₂—,—CO—NH—NH—CO—, —CO—NH—NH—CO—NR¹⁰—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, or—CO—N(CH₂—CO—OCH₃)—NH—CO—; R¹⁰ represents a hydrogen atom or a phenylgroup; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or1):

Formula: —A²—R¹¹  2)

(wherein A² represents —CO— or —SO₂—; R¹¹ represents:

a) A phenyl group which may be substituted by any number of the same ordifferent (halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxygroups, groups represented by formula —CH₂—NR¹²R¹³ or groups representedby the formula:

b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, andoptionally substituted with any of the same or different number of(halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups), or

c) A group represented by the formula: —CH₂—NR¹⁵R¹⁶,

where R¹², R¹³, R¹⁴ and R¹⁵, identical or different groups, representhydrogen atoms or C₁-C₆ lower alkyl groups and R¹⁶ represents (a phenylgroup or a phenylalkyl group), which may be substituted by any number ofthe same or different halogen atoms, C₁-C₆ lower alkyl group, or C₁-C₆lower alkoxy group):

Formula: —(CH₂)_(n)—R¹⁷  3)

(in the formula, R¹⁷ is a group which may be substituted at any possiblesites by any number of the same or different (halogen atoms, hydroxygroups, C₁-C₆ lower alkyl groups, or C₁-C₆ lower alkoxy groups),representing

a hydrogen atom, cyano group, C₂-C₇ alkoxycarbonyl group, C₁-C₆hydroxyalkyl group, C₁-C₆ lower alkynyl group, C₃-C₆ cycloalkyl group,C₃-C₇ alkenoyl group, a group represented by the formula:—(CHOH)CH₂OR¹⁸, a group represented by the formula: —CO—NH—NH—CO—OR¹⁹, agroup represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

in which n represents an integer of 1-4; R¹⁸ is C₁-C₆ lower alkyl group,C₂-C₆ lower alkenyl group, or C₂-C₆ lower alkynyl group and R¹⁹represents a C₁-C₆ lower alkyl group):

Formula: —(CH₂)_(r)—A³—R²⁰  4)

(wherein r represents an integer of 0-3; A³ represents a single bond,—CO—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NH—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—,—(CHOH)—CH₂—, or —(CHOH)—CH₂OCH₂—; R²⁰ represents an aromaticheterocyclic group containing 1-3 heteroatoms, selected from oxygenatoms, sulfur atoms, and/or nitrogen atoms in which the aromaticheterocyclic group may be substituted by any number of the same ordifferent (halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxygroups, or pyrrolyl groups) or may be condensed with a benzene ring toform a condensed ring):

Formula: —CH₂—CO—NR²¹R²²  5)

(wherein R²¹ represents a hydrogen atom or C₁-C₆ lower alkyl group; R²²represents a hydrogen atom, C₁-C₆ lower alkyl group, a group representedby the formula:

a group represented by the formula:

or R²¹ and R²² may be taken together with the nitrogen to form a 4 to7-membered saturated heterocycles, which may contain an oxygen atom,sulfur atom, or another nitrogen atom; where s represents 0 or 1; trepresents an integer of 0-2; R²³ represents a hydrogen atom, hydroxygroup, phenyl group, C₁-C₆ lower alkyl group, or C₁-C₆ lower alkoxygroup; R²⁴ represents a hydrogen atom or phenyl group which may besubstituted by hydroxy group; R²⁵ represents a hydrogen atom, phenylgroup (which may be substituted by hydroxy group), C₂-C₇ alkoxycarbonylgroup, C₁-C₆ lower alkyl group, C₁-C₆ alkylthio group, or 3-indolylgroup; and R²⁶ represents a hydroxy group, amino group, C₁-C₆ loweralkoxy group, or phenyalkyloxy group):

A hydrogen atom, C₁-C₆ alkanoyl group, or C₂-C₇ alkoxycarbonyl group.]

Here, the compounds represented by the above formula [II] haveactivities to inhibit the binding of chemokines such as MIP-1α and/orMCP-1 and the like to the receptor of a target cell and activities toinhibit physiological activities of cells caused by chemokines such asMIP-1α and/or MCP-1 and the lie.

PREFERRED EMBODIMENTS OF THE INVENTION

(1) On Invention 1

In the above formula [I], R¹ and R² are identical to or different fromeach other representing a phenyl group or an aromatic heterocyclic grouphaving 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/ornitrogen atoms, in which the phenyl or aromatic heterocyclic group maybe substituted by any number of halogen atoms, hydroxy groups, C₁-C₆lower alkyl groups, C₁-C₆ lower alkoxy groups, phenyl groups, benzylgroups, phenoxy groups, methylenedioxy groups, C₁-C₆ hydroxyalkylgroups, carboxy groups, C₂-C₇ alkoxycarbonyl groups, C₁-C₆ alkanoylaminogroups, dioxolanyl groups, or by group represented by the formula:—NR⁵R⁶, or else may be condensed with a benzene ring to form a condensedring. Unsubstituted aromatic heterocyclic groups having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms arespecifically, for example, thienyl, furyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrinidinyl,triazinyl, triazolyl, oxadiazolyl, thiadiazolyl group and the like,preferably including thienyl, furyl, pyrrolyl, and pyridyl groups.

The halogen atom as substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R² include fluorine atoms, chlorine atoms,bromine atoms, iodine atoms, suitably including fluorine atoms andchlorine atoms. The C₁-C₈ lower alkyl groups mean C₁-C₈ straight-chainor branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl,tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-methylpentyl,1-ethylbutyl, and the like, suitably specifically including, methyl,ethyl, and isopropyl groups. The C₁-C₆ lower alkoxy groups mean groupsconsisting of C₁-C₆ part of the aforementioned C₁-C₈ lower alkyl groupsand oxy groups, specifically, for example, methoxy group and ethoxygroup. The C₁-C₆ hydroxyalkyl groups are groups in which C₁-C₆ part ofthe aforementioned C₁-C₈ lower alkyl groups are substituted at their anypositions by a hydroxy group, preferably and specifically for example,hydroxymethyl group, 2-hydroxyethyl group, and the like. The C₂-C₇alkoxycarbonyl groups mean the aforementioned C₁-C₆ lower alkoxy groupsand carbonyl groups, preferably specifically for example, amethoxycarbonyl group and ethoxycarbonyl group. The C₂-C₇ loweralkanoylamino groups mean C₂-C₇ lower straight-chain or branchedalkanoylamino groups such as acetylamino, propanoylamino, butanoylamino,pentanoylamino, hexanoylamino, heptanoylamino, isobutyrylamino,3-methylbutanoylamino, 2-methylbutanoylamino, pivaloylamino,4-methylpentanoylamino, 3,3-dimethylbutanoylamino, 5-methylhexanoylaminogroup, and the like, where the preferred and specific example includesan acetylamino group. Condensed rings obtained by condensation with abenzene ring mean a ring obtained by the condensation with a benzenering of a phenyl group or an aromatic monocyclic heterocyclic ringhaving 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/ornitrogen atoms, at any possible sites, suitably and specifically forexample, naphthyl, indolyl, benzofuranyl, benzothienyl, quinolyl group,indolyl group, benzimidazolyl group.

R⁵ and R⁶ represent each independently hydrogen atoms, C₁-C₆ lower alkylgroups, or C₂-C₆ lower alkenyl groups. The C₁-C₆ lower alkyl groups arethe same as defined for the aforementioned C₁-C₆ part of the C₁-C₈ loweralkyl groups as substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², where the same examples can be givenfor the preferred specific examples. The C₂-C₆ lower alkenyl groups arefor example, C₂-C₆ straight-chain or branched alkenyl groups such asvinyl, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,4-methyl-3-pentenyl, and the like, where preferred specific examplesinclude allyl, 2-butenyl, and 3-butenyl group.

Furthermore above substituents for the phenyl or aromatic heterocyclicgroup and the condensed ring condenced with a benzene ring in R¹ and R²are optionally substituted by any substituents independently selectedfrom halogen atoms, hydroxy groups, or C₁-C₆ lower alkoxy groups. Thehalogen atoms and C₁-C₆ lower alkoxy groups are the same as defined forthe aforementioned substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², and the same examples can be listed aspreferred specific examples.

R¹ in the above formula [I] represents a hydrogen atom, hydroxy group,cyano group, C₁-C₆ lower alkoxy group, or C₂-C₇ lower alkanoyloxy group.The C₁-C₆ lower alkoxy groups are the same as defined for the C₁-C₆lower alkoxy groups in the aforementioned substituents for a phenylgroup or an aromatic heterocyclic group in R¹ and R²; where the sameexamples can be given for their preferred specific examples. The C₂-C₇lower alkanoyloxy groups mean C₂-C₇ lower straight-chain or branchedalkanoyloxy groups such as acetyloxy, propanoyloxy, butanoyloxy,pentanoyloxy, hexanoyloxy, heptanoyloxy, isobutyryloxy,3-methylbutanoyloxy, 2-methylbutanoyloxy, pivaloyloxy,4-methylpentanoyloxy, 3,3-dimethylbutanoyloxy, 5-methylhexanoyloxygroup, and the like, where the preferred and specific example includesan acetyloxy group. Preferred specific examples for R³ include ahydrogen atom and hydroxy group.

In the above formula [I], j represents an integer of 0-3. If R³represents a hydrogen atom, j is not 0. It is particularly preferred forj to be 2.

k in the above formula [I] represents 2 or 3; it is particularlypreferred to use a homopiperazine derivative in which k is 3.

R⁴ in the above formula [I] represents a group represented by:

Formula: —A¹—R⁷,  1)

Formula: —A²—R¹¹,  2)

Formula: —(CH₂)_(n)—R¹⁷,  3)

Formula: —(CH₂)_(r)—A³—R²⁰, or  4)

Formula: —(CH₂)—CO—NR²¹—R²².  5)

Here —CO— represents a carbonyl group. It is particularly preferred forR⁴ to be represented by formula 1): —A¹—R⁷ or formula 4):—(CH₂)_(r)—A³R²⁰.

R⁷ represents a phenyl group which may be substituted by any number ofthe same or different (halogen atoms, hydroxy groups, amino groups,C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups, cyano groups, nitrogroups, trifluoromethyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇alkanoyl groups, C₁-C₆ alkylsulfonyl groups, trifluoromethylsulfonylgroups, phenylsulfonyl groups (which may be substituted with a hydroxygroup), 1-pyrrolylsulfonyl groups, C₁-C₆ hydroxalkylsulfonyl groups,C₁-C₆ alkanoylamino groups, or a group represented by the formula:—CONR⁸R⁹). However, if R³ represents a hydrogen atom, the substituentfor a phenyl in R⁷ is not a hydroxy, C₁-C₆ lower alkyl, or C₁-C₆ loweralkoxy; if R³ is a hydrogen atom and k=2, R⁷ is not an unsubstitutedphenyl group; if R³ represents a cyano group, R⁷ is not unsubstitutedand the substituent for a phenyl in R⁷ is not a halogen atom, C₁-C₆lower alkyl, or C₁-C₆ lower alkoxy group.

The halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups,C₂-C₇ alkoxycarbonyl groups, and C₂-C₇ alkanoylamino groups assubstituents for a phenyl in R⁷ are the same as defined for theaforementioned substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², and the same examples can be listed aspreferred specific examples. The C₂-C₇ lower alkanoyl groups mean C₂-C₇lower straight-chain or branched alkanoyl groups such as acetyl,propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, isobutyryl,3-methylbutanoyl, 2-methylbutanoyl, pivaloyl, 4-methylpentanoyl,3,3-dimethylbutanoyl, 5-methylhexanoyl group, and the like, where thepreferred and specific example includes an acetyl group. The C₁-C₆alkylsulfonyl groups mean those consisting of the aforementioned C₁-C₆part of the C₁-C₆ lower alkyl groups and sulfonyl groups, preferably andspecifically, for example, a methylsulfonyl group. The phenylsulfonylgroups may be substituted with a hydroxy group at any position. TheC₁-C₆ hydroxyalkylsulfonyl groups mean those consisting of theaforementioned C₁-C₆ hydroxyallyl groups and sulfonyl groups, preferablyand specifically, for example, a (2-hydroxyethyl) sulfonyl group. R⁸ andR⁹, the same or different groups, represent hydrogen atoms or C₁-C₆lower alkyl groups. The C₁-C₆ lower alkyl groups as R⁸ and R⁹ are thesame as defined for the aforementioned C₁-C₆ part of the C₁-C₈ loweralkyl groups as substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², and the same examples are listed fortheir preferred specific examples.

A¹ is a group represented by the formula: —(CH₂)_(m)— or a grouprepresented by formula: —(CH₂)_(p)—G—(CH₂)_(q)— in which G represents G¹or G²; G¹ represents —O—, —CO—, —SO₂—, —CO—O—, —CONH—, —NHCO—, —NHCONH—,or —NH—SO₂—; G² represents —(C═NH)NH—SO₂—, —CO—NH—NH—CO—,—CO—NH—NH—CO—NR¹⁰—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, or—CO—N(CH₂—CO—OCH₃)—NH—CO—; R¹⁰ represents a hydrogen atom or a phenylgroup; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or1); however, if R³ is a hydrogen atom, G¹ is not —O— or —CO—; if R³represents a hydrogen atom and if k=2, m is not 0. In the above formula,—CO— means a carbonyl group and —SO₂— means a sulfonyl group. PreferredA¹ groups are specifically, for example, those represented by theformula —(CH₂)_(m)—, with m being preferably 1. Preferred A¹ groups arealso specifically, for example, —(CH₂)_(p)—CO—NH—NH—CO—(CH₂)_(q)—,—(CH₂)_(p)—CO—NH—NH—CO—NH—(CH₂)_(q)—;—(CH₂)_(p)—CO—NH—CH₂—CO—(CH₂)_(q)—; with p being preferably 1.

A² represents —CO— (carbonyl group ) or —SO₂— (sulfonyl group).

R¹¹ represents:

a) A phenyl group which may be substituted by any number of the same ordifferent (halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxygroups, groups represented by formula —CH₂—NR¹²R¹³ or groups representedby the formula:

b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, andoptionally substituted with any of the same or different number of(halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups), or

c) A group represented by the formula: —CH₂—NR¹⁵R¹⁶.

However if R³ represents a hydrogen atom, the substituent group for aphenyl group in R¹¹ is not a C₁-C₆ lower alkoxy group; if R³ representsa hydrogen atom and k is 2, R¹¹ is not a substituted or unsubstitutedphenyl group. The halogen atoms, C₁-C₆ lower alkyl groups, or C₁-C₆lower alkoxy groups as substituents for the groups in R¹¹ are the sameas defined for the aforementioned substituents for a phenyl group or anaromatic heterocyclic group in R¹ and R², and the same examples can begiven as preferred specific examples.

Specific examples for R¹¹ in which the aromatic monocyclic heterocyclicgroup is unsubstituted can be the same specific examples for thearomatic heterocyclic groups with no substituents in R¹ and R².Preferred examples specifically include a pyridyl group.

R¹², R¹³, R¹⁴ and R¹⁵ represent each independently hydrogen atoms orC₁-C₆ lower alkyl groups. The C₁-C₆ lower alkyl groups are of the samedefinition for the aforementioned C₁-C₆ part of the C₁-C₈ lower alkylgroups as substituents for a phenyl group or an aromatic heterocyclicgroup in R¹ and R², where the same examples can be listed as preferredspecific examples.

R¹⁶ represents a (phenyl group or phenylalkyl group) which may besubstituted by any number of the same or different (halogen atoms, C₁-C₆lower alkyl groups, or C₁-C₆ lower alkoxy group). The halogen atom,C₁-C₆ lower alkyl group or C₁-C₆ lower alkoxy group as substituents arethe same as defined for the aforementioned substituents for a phenylgroup or an aromatic heterocyclic group in R¹ and R², where the sameexamples can be given as preferred specific examples. The phenylalkylgroup means a group consisting of a phenyl group and a C₁-C₆ alkylenegroup, preferably and specifically for example, a benzyl group.

R¹⁷ is a group which may be substituted at any possible sites by anynumber of the same or different (halogen atoms, hydroxy groups, C₁-C₆lower alkyl groups, or C₁-C₆ lower alkoxy groups), representing

a hydrogen atom, cyano group, C₂-C₇ alkoxycarbonyl group, C₁-C₆hydroxyalkyl group, C₁-C₆ lower alkynyl group, C₃-C₆ cycloalkyl group,C₂-C₇ alkenoyl group, a group represented by the formula:—(CHOH)CH₂OR¹⁸, a group represented by the formula: —CO—NH—NH—CO—OR¹⁹, agroup represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

If, however, R³ represents a hydrogen atom, R¹⁷ is not a hydrogen atom,C₂-C₇ alkoxycarbonyl group, or C₁-C₆ hydroxyalkyl group. R¹⁷ may bebonded at any possible site to an alkylene group —(CH₂)_(n)—. The C₂-C₇alkoxycarbonyl and C₁-C₆ hydroxyalkyl groups are the same as defined forthe aforementioned substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², where the same examples may be given aspreferred specific examples. The C₁-C₆ lower alkynyl group means a C₂-C₆straight-chain or branched alkynyl groups such as ethynyl, 1-propynyl,2-propynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl,1-methyl-4-pentynyl group, and the like, preferably and specifically,for example, ethynyl group and 1-propynyl group. The C₃-C₆ cycloalkylgroups mean cyclic alkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl groups and the like. The C₃-C₇ lower alkenoylgroup means a C₃-C₇ straight-chain or branched alkenoyl groups such aspropenoyl, 2-metylpropenoyl, 2-buenoyl, 3-butenoyl, 2-methyl-3-butenoyl,3-methyl-2-butenoyl, 2-pentenoyl, 4-pentenoyl, 2-methyl-2-pentenoyl,2,2-dimethyl-4-pentenoyl, 2-hexenoyl, 3-hexenoyl, 6-heptenoyl, and thelike, preferably and specifically, for example propenoyl and2-metylpropenoyl group.

The halogen atom, C₁-C₆ lower alkyl group or C₁-C₆ lower alkoxy groupsas substituents for R¹⁷ are the same as defined for the aforementionedsubstituents for a phenyl group or an aromatic heterocyclic group in R¹and R², and the same examples can be given as preferred specificexamples.

R¹⁸ represents a C₁-C₆ lower allkyl group, C₂-C₆ lower alkenyl group, orC₂-C₆ lower alkynyl group. The C₁-C₆ lower alkyl groups are the same asdefined for the aforementioned C₁-C₆ part of the C₁-C₆ lower alkylgroups as substituents for a phenyl group or an aromatic heterocyclicgroup in R¹ and R², where the same examples can be given as preferredspecific examples. The C₂-C₆ lower alkenyl groups are the same as theC₂-C₆ lower alkenyl groups in the aforementioned R⁵ and R⁶, where thepreferred examples are specifically allyl, 2-butenyl, and 3-butenylgroup. The C₂-C₆ lower alkynyl groups are the same as the C₂-C₆ loweralkynyl groups in the aforementioned R¹⁷ where the preferred examplesare specifically 2-propynyl group and 3-butynyl group.

R¹⁹ represents a C₁-C₆ lower alkyl group. Here, the C₁-C₆ lower alkylgroup is the same as defined for the aforementioned C₁-C₆ part of theC₁-C₆ lower alkyl groups as substituents for a phenyl group or anaromatic heterocyclic group in R¹ and R², where the same examples can begiven as preferred specific examples.

n is an integer of 1-4. It is particularly preferred for the n to be 1or 2.

A³ represents a single bond, —CO—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NH—,—CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, —(CHOH)—CH₂—, or —(CHOH)—CH₂OCH₂—.However, if R³ represents a hydrogen atom. A³ is not a single bond.Here, —CO— means a carbonyl group and —SO₂— means a sulfonyl group. A³is preferably a single bond or —CO—NH—NH—CO—.

R²⁰ represents an aromatic heterocyclic group containing 1-3heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogenatoms in which the aromatic heterocyclic group may be substituted by anynumber of the same or different (halogen atoms, C₁-C₆ lower alkylgroups, C₁-C₆ lower alkoxy groups, or pyrrolyl groups) or may becondensed with a benzene ring to form a condensed ring. As to specificexamples in which the aromatic monocyclic heterocyclic group R²⁰ has nosubstitution, the same specific example can be given as in the caseswith no substituents on the aromatic heterocyclic rings in R¹ and R²;preferred examples are specifically a pyridyl group and is oxazolylgroup.

The halogen atom, C₁-C₆ lower alkyl group, or C₁-C₆ lower alkoxy groupas substituents for the aromatic heterocyclic group in R²⁰ are the sameas defined for the aforementioned substituents for a phenyl group or anaromatic heterocyclic group in R¹ and R², where the same examples can begiven as suitable specific examples. The condensed ring obtained bycondensation with a benzene ring in R²⁰ is the same as defined for thecondenced ring in R¹ and R², where the same examples can be given assuitable specific examples.

r is an integer of 0-3. However, if R³ represents a hydrogen atom, r isnot 0. In particular, it is preferred for r to be 1.

R²¹ represents a hydrogen atom or C₁-C₆ lower alkyl group. R²²represents a hydrogen atom, C₁-C₆ lower alkyl group, a group representedby the formula:

a group represented by the formula:

or may be taken together with the nitrogen to form a 4 to 7-memberedsaturated heterocycles, which may contain an oxygen atom, sulfur atom,or another nitrogen atom. The C₁-C₆ lower alkyl groups in R²¹ and R²²are the same as defined for the aforementioned C₁-C₆ part of the C₁-C₈lower alkyl groups as substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², where the same examples can be givenfor the preferred specific examples. Saturated heterocyclic ringsconsisting of R²¹, R²², and the nitrogen include azetidine, pyrrolidine,piperidine, perhydroazepine, morpholine, thiamorpholine, piperazine,homopiperazine, and the like; preferred specific examples includepiperidine, morpholine, and thiamorpholine.

s represents 0 or 1 and t represents an integer of 0-2.

R²³ represents a hydrogen atom, hydroxy group, phenyl group, C₁-C₆ loweralkyl group, or C₁-C₆ lower alkoxy group. The C₁-C₆ lower alkyl groupand C₁-C₆ lower alkoxy groups as R²³ are the same as defined for theaforementioned substituents for a phenyl group or an aromaticheterocyclic group in R¹ and R², where the same examples can be givenfor the preferred specific examples.

R²⁴ represents a hydrogen atom or phenyl group, where the phenyl groupmay be substituted by hydroxy group at any position.

R²⁵ represents a hydrogen atom, phenyl group. C₂-C₇ alkoxycarbonylgroup, C₁-C₆ lower alkyl group, C₁-C₆ alkylthio group, or 3-indolylgroup, where the phenyl group may be substituted by hydroxy group at anyposition. The C₂-C₇ alkoxycarbonyl group and C₁-C₆ lower alkyl group asR²⁵ are the same as defined for the aforementioned substituents for aphenyl group or an aromatic heterocyclic group in R¹ and R², where thesame examples can be given for the preferred specific examples. TheC₁-C₆ alkylthio group as R²⁵ means a group consisting of thio group andC₁-C₆ part of the aforementioned C₁-C₈ lower alkyl groups forsubstituent in R¹ and R², specifically, for example, methylthio groupand ethylthio group.

R²⁶ represents a hydroxy group, amino group, C₁-C₆ lower alkoxy group,or phenylalkyloxy group. The C₁-C₆ lower alkoxy group is the same asdefined for the aforementioned C₁-C₆ lower alkoxy group as substituentfor a phenyl group or an aromatic heterocyclic group in R¹ and R², wherethe same examples can be given for the preferred specific examples. Thephenylalkyl group means a group consisting of a phenyl group, a C₁-C₆alkylene group, and a oxy group, preferably and specifically forexample, a benzyl oxy group.

(2) On Invention 2

R¹, R², R³, j, and k in the above formula [II] are as the same asdefined in the respective terms for the above formula [I] and the sameexamples can be listed for their preferred specific examples. R⁴ in theabove formula [II] includes R⁴ defined in the respective terms for theabove formula [I], where the same examples can be listed for theirpreferred specific examples, and furthermore R⁴ in the above formula[II] represents a hydrogen atom, C₁-C₆ alkanoyl group, or C₂-C₇alkoxycarbonyl group. However, the above formula [II] does not involvethe same limitations as made in the above formula [I] with respect tocases where R³ represents a hydrogen atom, where R³ represents ahydrogen atom and k represents 2, and where R³ represents cyano group.

The cyclic diamine derivative represented by the formula [II] above orits pharmacologically acceptable acid adduct can be used to prepare achemokine receptor antagonist preparation of the present invention byformulating the therapeutically required amount and a carrier and/ordiluent into a pharmaceutical composition. Thus, the cyclic diaminederivative shown by the above formula [II] or its pharmacologicallyacceptable acid adduct can be administered orally or by parenterally,for example, intravenously, subcutaneously, intramuscularly,percutaneously or intrarectally.

The oral administration can be accomplished in the form of tablets,pills, granules, powder, solution, suspension, capsules, etc.

The tablets for example can be prepared using a vehicle such as lactose,starch and crystallized cellulose; binder such ascarboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone;disintegrator such as sodium alginate, sodium bicarbonate and sodiumlauryl sulfate, etc.

Pills, powder and granule preparations can be prepared by a standardmethod using the vehicles mentioned above. Solution or suspension can beprepared by a standard method using glycerin ester such as tricaprylinand triacetin or alcohols such as ethanol. Capsules can be made bycharging granules, powder or solution in gelatin, etc.

Subcutaneous, intramuscular or intravenous preparations can be preparedas an injection using aqueous or nonaqueous solution. Aqueous solutionfor example may include isotonic sodium chloride solution. Nonaqueoussolutions may include for example, propyleneglycol, polyethyleneglycol,olive oil, ethyl oleate, etc., and optionally, one can add antisepticsand stabilizers. For injection, one can be sterilized by filtrationthrough a bacterial filter or combination of disinfectant.

Percutaneous administration may be in the form of an ointment or cream,and ointment can be prepared in the standard manner using fatty oilssuch as castor oil and olive oil. or Vaseline, while creams can be madeusing fatty oils or emulsifying agent such as diethylene glycol andsorbitan esters of fatty acid.

For intrarectal administration, one can use standard suppositories usinggelatin soft capsules, etc.

The cyclic diamine derivative of the present invention or itspharmacologically acceptable acid adduct is administered at a dose thatvaries depending on the type of disease, route of administration, ageand sex of patient, and severity of disease, but is likely to be 1-500mg/day in an average adult.

(3) Matter Common Throughout Invention 1 and Invention 2

Preferred specific examples for the cyclic diamine derivatives in theabove formula [I] or formula [II] include compounds having eachsubstituent as shown in the following Tables 1.1-1.25.

Table 1.1-Table 1.25

TABLE 1.1 Com- pound No. R¹ R² R³ j k R⁴ 1

CN 2 2

2

CN 2 3

3

CN 2 3

4

CN 2 3

5

H 0 3

6

H 1 3

7

H 2 2

8

H 2 2

9

H 2 2

10

H 2 2

11

H 2 2

12

H 2 2

13

H 2 2

14

H 2 2

15

H 2 3

16

H 2 3

17

H 2 3

18

H 2 3

19

H 2 3

20

H 2 3

21

H 2 3

22

H 2 3

23

H 2 3

24

H 2 3

25

H 2 3

26

H 2 3

27

H 2 3

28

H 2 3

29

H 2 3

30

H 2 3

31

H 2 3

32

H 2 3

33

H 2 3

34

H 2 3

35

H 2 3

36

H 2 3

37

H 2 3

38

H 2 3

39

H 2 3

40

H 2 3

41

H 2 3

42

H 2 3

43

H 2 3

44

H 2 3

45

H 2 3

46

H 2 3

47

H 2 3

48

H 2 3

49

H 2 3

50

H 2 3

51

H 2 3

52

H 2 3

53

H 2 3

54

H 2 3

55

H 2 3

56

H 2 3

57

H 2 3

58

H 2 3

59

H 2 3

60

H 2 3

61

H 2 3

62

H 2 3

63

H 2 3

64

H 2 3

65

H 2 3

66

H 2 3

67

H 2 3

68

H 2 3

69

H 2 3

70

H 2 3

71

H 2 3

72

H 2 3

73

H 2 3

74

H 2 3

75

H 2 3

76

H 2 3

77

H 2 3

78

H 2 3

79

H 2 3

80

H 2 3

81

H 2 3

82

H 2 3

83

H 2 3

84

H 2 3

85

H 2 3

86

H 2 3

87

H 2 3

88

H 2 3

89

H 2 3

90

H 2 3

91

H 2 3

92

H 2 3

93

H 2 3

94

H 2 3

95

H 2 3

96

H 2 3

97

H 2 3

98

H 2 3

99

H 2 3

100

H 2 3

101

H 2 3

102

H 2 3

103

OCH₃ 2 3

104

OCH3 2 3

105

OCOCH₃ 2 3

106

OH 2 3

107

OH 2 3

108

OH 2 3

109

OH 2 3

110

OH 2 3

111

OH 2 3

112

OH 2 3

113

OH 2 3

114

OH 2 3

115

OH 2 3

116

OH 2 3

117

OH 2 3

118

OH 2 3

119

OH 2 3

120

OH 2 3

121

OH 2 3

122

OH 2 3

123

OH 2 3

124

OH 2 3

125

OH 2 3

126

OH 2 3

127

OH 2 3

128

OH 2 3

129

OH 2 3

130

OH 2 3

131

OH 2 3

132

OH 2 3

133

OH 2 3

134

OH 2 3

135

OH 2 3

136

OH 2 3

137

OH 2 3

138

OH 2 3

139

OH 2 3

140

OH 2 3

141

OH 2 3

142

OH 2 3

143

OH 2 3

144

H 2 3

145

OH 2 3

146

OH 2 3

147

OH 2 3

148

OH 2 3

149

OH 2 3

150

OH 2 3

151

OH 2 3

152

OH 2 3

153

OH 2 3

154

OH 2 3

155

OH 2 3

156

OH 2 3

157

OH 2 3

158

OH 2 3

159

OH 2 3

160

OH 2 3

161

OH 2 3

162

OH 2 3

163

OH 2 3

164

OH 2 3

165

OH 2 3

166

OH 2 3

167

OH 2 3

168

OH 2 3

169

OH 2 3

170

OH 2 3

171

OH 2 3

172

OH 2 3

173

OH 2 3

174

OH 2 3

175

OH 2 3

176

OH 2 3

177

OH 2 3

178

OH 2 3

179

OH 2 3

180

OH 2 3

181

OH 2 3

182

OH 2 3

183

OH 2 3

184

OH 2 3

185

OH 2 3

186

OH 2 3

187

OH 2 3

188

OH 2 3

189

OH 2 3

190

OH 2 3

191

OH 2 3

192

OH 2 3

193

OH 2 3

194

OH 2 3

195

OH 2 3

196

OH 2 3

197

OH 3 3

198

OH 3 3

199

H 2 3

200

H 2 3

201

H 2 3

202

H 2 3

203

H 2 3

204

H 2 3

205

H 2 3 —(CH₂)₂CH₃ 206

H 2 3

207

H 2 3

208

H 2 3

209

H 2 3 —(CH₂)₂—CO₂CH₃ 210

H 2 3 —CH₂C≡CCH₃ 211

H 2 3

212

H 2 3

213

H 2 3 —(CH₂)₄—C≡N 214

H 2 3 —(CH₂)₂—C≡N 215

H 2 3 —(CH₂)₃—C≡N 216

H 2 3

217

H 2 3 —CH₂—C≡N 218

H 2 3

219

H 2 3

220

H 2 3 —CH₂C≡CH 221

H 2 3

222

H 2 3

223

H 2 3

224

H 2 3

225

H 2 3

226

H 2 3

227

OH 2 3

228

OH 2 3

229

OH 2 3

230

OH 2 3

231

OH 2 3

232

OH 2 3

233

CN 2 3

234

CN 2 3

235

H 2 3

236

H 2 3

237

H 2 3

238

H 2 3

239

H 2 3

240

H 2 3

241

H 2 3

242

H 2 3

243

H 2 3

244

H 2 3

245

H 2 3

246

H 2 3

247

H 2 3

248

H 2 3

249

H 2 3

250

H 2 3

251

H 2 3

252

H 2 3

253

H 2 3

254

H 2 3

255

H 2 3

256

H 2 3

257

H 2 3

258

OH 2 3

259

OH 2 3

260

OH 2 3

261

OH 2 3

262

OH 2 3

263

OH 2 3

264

CN 2 3

265

H 2 3

266

H 2 3

267

H 2 3

268

H 2 3

269

H 2 3

270

H 2 3

271

H 2 3

272

H 2 3

273

H 2 3

274

H 2 3

275

H 2 3

276

H 2 3

277

H 2 3

278

H 2 3

279

H 2 3

280

H 2 3

281

H 2 3

282

H 2 3

283

H 2 3

284

H 2 3

285

H 2 3

286

H 2 3

287

H 2 3

288

H 2 3

289

H 2 3

290

H 2 3

291

H 2 3

292

H 2 3

293

OH 2 3

294

OH 2 3

295

OH 2 3 —H 296

OH 2 3

297

H 2 3

298

H 2 3

299

H 2 3

The present invention can also use acid adducts of the cyclic diaminederivatives where such acids include, for example, mineral acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,carbonic acid, and the like, as well as organic acids such as citricacid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid,trifluoroacetic acid, and the like.

The present invention may use racemates and all possible opticallyactive forms of the cyclic diamine derivatives represented by the aboveformula [I] or [II].

Compounds represented by the above general formula [I] and/or [II] canbe synthesized by any of the general preparations given below.

(Preparation 1)

A preparation which call for treating one equivalent of a cyclic diaminederivative represented by the formula [III] below:

[where R¹, R², R³, j, and k are as defined respectively in the aboveformula [I] or [II]] with 0.1-10 equivalents of a compound representedby the formula [IV] below:

X¹—R⁴  [IV]

[wherein R⁴ is the same as defined for the R⁴ in the above formula [I]or [II]; X¹ is a halogen atom, alkylsulfonyloxy group, orarylsulfonyloxy group. R⁴ is not a group represented by the formula:—A²—R¹¹ in where A² and R¹¹ are the same as defined respectively in theabove formula [I] or [II]], either in absence or presence of solvent;

alternatively treating 1 equivalent of a cyclic diamine given by theformula [V] below:

[where R⁴ and k are the same as defined respectively in the aboveformula [I] or [II]], with 0.1-10 equivalents of a compound representedby the formula [VI] below:

[where R¹, R², R³, and j are the same as defined respectively in theabove formula [I] or [II]; X¹ represents a halogen atom,alkylsulfonyloxy, or arylsulfonyloxy group] either in the absence orpresence of solvent.

Such reactions can be more smoothly run if a base is present. The basewhich may be used includes inorganic salts such as potassium carbonate,sodium carbonate, sodium hydrogencarbonate, and the like, or amines suchas triethylamine, diisopropylethylamine, and pyridine, and the like. Inaddition, the reactions in these preparations can also be promoted byiodide such as potassium iodide, sodium iodide, or the like.

X¹ in the above formulas [IV] and [VI] represents a halogen atom,alkylsulfonyloxy, or arylsulfonyloxy group. Such halogen atoms includepreferably chlorine, bromine, and iodine atoms. Suitable specificexamples for the alkylsulfonyloxy groups include methylsulfonyloxy andtrifluoromethylsulfonyloxy group and the like. A preferred specificexample for the arylsulfonyloxy group includes a tosyloxy group.

(Preparation 2)

A preparation which calls for treating 1 equivalent of a cyclic diaminederivative represented by the above formula [III] with 0.1-10equivalents of a carboxylic acid, sulfonic acid represented by theformula [VII] below:

HO—A²—R¹¹  [VII]

[where R¹¹ and A³ are the same as defined respectively in the aboveformulas [I] or [II]], or its reactive derivative, either in the absenceor presence of solvent.

The reactive derivatives for the carboxylic acids or sulfonic acids inthe above formula [VII] include highly reactive carboxylic or sulfonicacid derivatives, which are usually used in synthetic organic chemistry,such as acid halides, acid anhydrides, mixed acid anhydrides. If estersare used, the reaction can be run smoothly by activating the cyclicdiamine derivative represented by the above general formula [III], forexample, by using triethylaluminum.

Such reactions can be more smoothly run by using suitable amounts of adehydrating agent such as molecular sieve, condensing agents such asdicyclohexyl carbodiimide,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, andthe like, or bases similar to those used in the above preparation 1.

(Preparation 3)

A preparation which calls for treating 1 equivalent of a cyclic diaminerepresented by the above formula [III], with 0.1-10 equivalents of analdehyde represented by the formula [VIII] below:

R²⁷—(CH₂)_(z)—CHO  [VIII]

[where in the formula R¹⁷ represents either R⁷, R¹⁷, or R²⁰ of the aboveformula [I] or [II]; z represents an integer of 0-3], either in theabsence or the presence of solvent under reductive conditions, or elsetreating 1 equivalent of a compound represented by the above formula [V]with 0.1-10 equivalents of an aldehyde represented by the formula [IX]below:

[where in the formula R¹, R², R³, and j are the same as definedrespectively in the above formulais [I] or [II]], either in the absenceor the presence of solvent under reductive conditions.

Such reactions are in general called reductive amination reactions andsuch reductive conditions may be generated by catalytic hydrogenationusing a catalyst containing a metal such as palladium, platinum, nickel,rhodium, or the like, using complex hydrides such as lithium aluminumhydride, sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride, and the like, boranes, or electrolytic reduction,and the like.

(Preparation 4)

A preparation which calls for treating 1 equivalent of a cyclic diaminederivative represented by the formula [X] below:

[where in the formula j, k, and R⁴ are the same as defined respectivelyfor the above formula [I] or [II] and R²⁸ represents a C₁-C₆ lower alkylgroup] or 1 equivalent of a cyclic diamine derivative represented by theformula [XI] below:

[where R¹, j, k, and R⁴ are the same as defined respectively for theabove formula [I] or [II]], with 0.1-10 equivalents of an organometallicreagent represented by the formula [XII] below:

R²⁹—M  [XII]

[wherein the formula R²⁹ is the same as defined for the R¹ and R² in theabove formula [I] or [II]; M is a metal atom or its halide or complex]in the presence of solvent.

The organometallic reagents used in such preparations may be thosesuitably selected organometallic reagents known to cause a nucleophilicreaction toward esters and/or ketones in general in synthetic organicchemistry, such as Grignard reagents (M=MgX²), organolithium reagents(M=Li), organocerium reagents (M=CeX₂ ²,) (X² represents a halogenatom). These organometallic reagents may be prepared by known methodsfrom the corresponding halides. The halides preferably includechlorides, bromides, iodides.

If the substrates submitted to each of the above preparations contains asubstituent which reacts under each reaction condition in general insynthetic organic chemistry or is thought to adversely affect thereaction, that functional group can be protected by a known suitableprotecting group followed by the reaction of the above preparations anddeprotection using a known procedure to ado obtain the desired compound.

Each of the above preparations may use solvents for the reaction such ashalogenated hydrocarbons such as dichloromethane, chloroform, or thelike, aromatic hydrocarbons such as benzene, toluene, and the like,ethers such as diethyl ether, tetrahydrofuran, or the like, esters suchas ethyl acetate, aprotic polar solvents such as dimethylformamide,dimethyl sulfoxide, acetonitrile, and the like, alcohols such asmethanol, ethanol, isopropyl alcohol, and the like.

The reaction temperature in either of the preparations should be in therange of −78-+150° C., preferably 0° C.-100° C. After completion of thereaction, the usual isolation and purification operations such asconcentration, extraction, recrystallization, chromatography, and thelike may be used, to isolate the desired cyclic diamine derivativesrepresented by the above formula [I] or [II]. These can be convertedinto pharmacologically acceptable acid adducts by the usual method.

Potential Industrial Utilities

The chemokine receptor antagonist, which contain the cyclic diaminederivative or its pharmacologically acceptable acid adducts of thisinvention, which inhibits chemokines such as MIP-1α and/or MCP-1 and thelike from action on target cells, are useful as therapeutic agentsand/or preventive preparation for diseases such as atherosclerosis,rheumatic arthritis, psoriasis, asthma, ulcerative colitis,glomerulonephritis, multiple sclerosis, pulmonary fibrosis, myocarditis,and the like, in which tissue infiltration of blood monocytes,lymphocytes, and the like plays a major role in the initiation,progression, and maintenance of the disease.

EXAMPLES

The present invention is now specifically described by the followingexamples. However, the present invention is not limited to thesecompounds described in these examples. Compound numbers in theseexamples represent numbers attached to these compounds listed assuitable specific examples in Tables 1.1-1.18.

Example 1 Synthesis of1-(3,3-Diphenylpropyl)-4-(4-nitrobenzyl)homopiperazine (Compound No. 23)

A mixture of 120 mg of homopiperazine, 206 mg of homopiperazinedihydrochloride, and 3 mL of ethanol was heated to 70° C. to prepare asolution. 375 mg of sodium iodide and 287 mg of 3,3-diphenylpropylmethanesulfonate were added sequentially to the solution and the mixturewas stirred at 70° C. for 14 hours. The mixture was allowed to cool toroom temperature and the ethanol was removed under reduced pressure,followed by adding 20 mL of 2N aqueous sodium hydroxide solution andextracting with 20 mL×2 of ethyl acetate. The organic layers werecombined, washed with 20 mL of saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated to give1-(3,3-diphenylpropyl)homopiperazine.

The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3mL of acetonitrile followed by adding 213 mg of 4-nitrobenzyl bromideand 144 mg of potassium carbonate. The mixture was stirred at 70° C. for14 hours and allowed to cool to room temperature and the solvent wasremoved under reduced pressure. 20 mL of aqueous 2N sodium hydroxide wasadded and the mixture was extracted with 20 mL×2 of ethyl acetate. Theorganic layers were combined, washed with 20 mL of saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered,concentrated, and purified by column chromatography (silica gel, ethylacetate) to obtain 255 mg of the titled compound. This was treated witha hydrogen chloride solution in ether and the solvent was removed underreduced pressure; and the residue was dried to obtain the hydrochloridesalt of the titled compound.

Compound No. 23 (Free Base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.73-1.82 (m, 2H), 2.16-2.25 (m, 2H), 2.40-2.46 (m, 2H),2.64-2.71 (m, 8H), 3,71 (s, 2H), 4.01 (t, J=7.6 Hz, 1H), 7.13-7.19 (m,2H), 7.19-7.31 (m, 8H), 7.50 (d, J=8.6 Hz, 2H), 8.16 (d, J=8.6 Hz, 2H).

Example 2 Preparation of 1-Benzyl-4-(3,3-diphenylpropyl)homopiperazine(Compound No. 15)

A mixture of 101 mg of homopiperazine, 175 mg of homopiperazinedihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution.0.115 mL of benzyl chloride was added and the mixture was stirred at 70°C. for 3 hours. After cooling to room temperature, ethanol was removedunder reduced pressure, and 20 mL of aqueous 2N sodium hydroxidesolution was added to the solution, which was extracted with 20 mL×2 ofethyl acetate. The organic layers were combined, washed with 20 mL ofsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated to give 1-benzyihomopiperazine.

The resulting benzyihomopiperazine was dissolved in 3 mL of ethanol, towhich were added 296 mg of 3,3-diphenylpropyl methanesulfonate and 136mg of potassium carbonate. The mixture was stirred at 70° C. for 15hours and it was cooled to room temperature and the solvent was removedunder reduced pressure. 20 mL of aqueous 2N sodium hydroxide was addedand the solution was extracted with 20 mL×2 of ethyl acetate. Theorganic layers were combined and washed with 20 mL of saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered,concentrated, and purified by column chromatography (silica gel, ethylacetate) to obtain 135 mg of the titled compound. This was treated witha hydrogen chloride solution in ether followed by removing the solventunder reduced pressure and drying to give the hydrochloride salt of thetitled compound.

Compound No. 15 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.71-1.81 (m, 2H), 2.16-2.25 (m, 2H), 2.39-2.45 (m, 2H),2.64-2.73 (m, 8H), 3,62 (s, 2H), 4.01 (t, J=7.9 Hz, 1H), 7.12-7.34 (m,15H).

Example 3 Preparation of 1-Benzoyl-4-(3,3-diphenylpropyl)homopiperazine(Compound No. 199)

A mixture of 126 mg of homopiperazine. 218 mg of homopiperazinedihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution.378 mg of sodium iodide and 289 mg of 3,3-diphenylpropylmethanesulfonate were added sequentially to the solution and thesolution was stirred at 70° C. for 15 hours. After the solution wascooled to room temperature, the ethanol was removed under reducedpressure followed by adding 20 mL of aqueous 2N sodium hydroxide andextracting with 20 mL×2 of ethyl acetate. The organic layers werecombined, washed with 20 mL of saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated to give1-(3,3-diphenylpropyl)homopiperazine.

The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3mL of dichloromethane, followed by adding 107 mg of triethylamine and140 mg of benzoyl chloride. After the mixture was stirred at roomtemperature for 6 hours, it was mixed with 20 mL of aqueous 2N sodiumhydroxide and extracted with 20 mL×2 of ethyl acetate. The organiclayers were combined, washed with 20 mL of saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered,concentrated, and purified by column chromatography (silica gel,hexane/ethyl acetate 4:6) to obtain 249 mg of the titled compound. Thiswas treated with a hydrogen chloride solution in ether and the solventwas removed under reduced pressure and the residue was dried to give thehydrochloride salt of the titled compound.

Compound No. 199 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.69-1.79 (m, 1H), 1.90-1.99 (m, 1H), 2.12-2.28 (m, 2H),2.35-2.48 (m, 2H), 2.54-2.61 (m, 2H), 2.64-2.69 (m, 1H), 2.75-2.30 (m,1H), 3.39-3.46 (m, 2H), 3.73-3.78 (m, 2H), 3,96-4.06 (m, 1H), 7.13-7.31(m, 10H), 7.35-7.39 (m, 5H).

Example 4 Preparation of1-[4-(Dimethylaminomethyl)benzoyl]-4-(3,3-diphenylpropyl)homopiperazine(Compound No. 202)

The same method as that of Example 1 was used to obtain1-(3,3-diphenylpropyl)homopiperazine.

The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mLof toluene under argon, followed by adding 0.65 mL of a 15%trimethylaluminum solution in hexane. The mixture was stirred at roomtemperature for 15 minutes, mixed with 187 mg of methyl4-(dimethylaminomethyl)benzoate, stirred at 60° C. for 22 hours. Themixture was cooled to room temperature, mixed with 2N hydrochloric acid,and stirred. 20 mL of aqueous 2N sodium hydroxide was added and themixture was extracted with 20 mL×2 of ethyl acetate. The organic layerswere combined, washed with 20 mL of saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered, concentrated, andpurified by column chromatography (silica gel, ethyl acetate/methanol6:4) to obtain 234 mg of the titled compound. This was treated with ahydrogen chloride solution in ether, the solvent was removed underreduced pressure and the residue was dried to give the hydrochloridesalt of the titled compound.

Compound No. 202 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.65-1.80 (m, 1H), 1.89-2.01 (m, 1H), 2.12-2.29 (m, 2H), 2.24 (s,6H), 2.35-2.48 (m, 2H), 2.52-2.60 (m, 2H), 2.60-2.70 (m, 1H), 2.74-2.79(m, 1H), 3,40-3.48 (m, 2H), 3.43 (s, 2H), 3.32-3.77 (m, 2H), 3.96-4.06(m, 1H), 7.16-7.52 (m, 14H).

Example 5 Preparation of1-(3,3-Diphenylpropyl)-4-(2-quinolylmethyl)homopiperazine (Compound No.237)

The same method as that of Example 1 was used to obtain1-(3,3-diphenylpropyl)homopiperazine.

The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mLof ethanol, mixed with 228 mg of 2-(chloromethyl)quinoline hydrochlorideand 141 mg of potassium carbonate, and stirred at 70° C. for 14 hours.The mixture was cooled to room temperature and the ethanol was removedunder reduced pressure, 20 mL of aqueous 2N sodium hydroxide was addedand the mixture was extracted with 20 mL×2 of ethyl acetate. The organiclayers were combined, washed with 20 mL of saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered,concentrated, and purified by column chromatography (silica gel, ethylacetate/methanol 95:5), to obtain 109 mg of the titled compound. Thiswas treated with a hydrogen chloride solution in ether and the solventwas removed under reduced pressure and the residue was dried to give thehydrochloride salt of the titled compound.

Compound No. 237 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.76-1.86 (m, 2H), 2.18-2.27 (m, 2H), 2.42-2.49 (m, 2H),2.68-2.82 (m, 8H), 3.96 (s, 2H), 4.02 (t, J=7.6 Hz, 1H), 7.12-7.31 (m,1H), 7.50 (dd, j=7.9, 7.9 Hz, 1H), 7.65-7.72 (m, 2H), 7.79 (d, J=7.9 Hz,1H), 8.05 (d, J=8.3 Hz, 1H), 8.11 (d, J=8.6 Hz, 1H).

Example 6 Preparation of1-(3,3-Diphenylpropyl)-4-(7-methoxy-2H-chromene-2-one-4-ylmethyl)homopiperazine(Compound No. 206)

The same method as that of Example 5 was used except for the use of 70mg of 4-(bromomethyl)-7-methoxy-2H-chromene-2-one to give 303 mg of thetitled compound, and except for the use of ethanol/chloroform as thesolvent for the reaction. Furthermore, the same method as that ofExample 5 was used to obtain the hydrochloride salt of the titledcompound,

Compound No. 206 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.75-1.85 (m, 2H), 2.16-2.25 (m, 2H), 2.39-2.45 (m, 2H),2.62-2.79 (m, 8H), 3.72 (s, 2H), 3.87 (s, 3H), 4.02 (t, J=7.6 Hz, 1H),6.36 (s, 1H), 6.80-6.85 (m, 2H), 7.12-7.31 (m, 10H), 7.75 (d, J=9.6 Hz,1H).

Example 7 Preparation of1-(2-Benzimidazolylmethyl)-4-(3,3-diphenylpropyl)homopiperazine(Compound No. 207)

The same method as that of Example 5 was used except for the use of 165mg of 2-(chloromethyl)benzimidazole and 16 mg of sodium iodide topromote the reaction to give 91 mg of the titled compound, Furthermore,the same method as that of Example 5 was used to obtain thehydrochloride salt of the titled compound.

Compound No. 207 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.70-1.82(m, 2H), 2.19-2.29 (m, 2H), 2.43-2.50 (m, 2H), 2.65-2.73(m, 4H), 2.76-2.81 (m, 4H), 3.96 (s, 2H), 3.99 (t, J=7.6 Hz, 1H),7.14-7.31 (m, 14H), 7.60-7.85 (m, 1H).

Example 8 Preparation of1-(2,2-Diphenylethyl)-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 6)

A mixture of 120 mg of homopiperazine, 216 mg of homopiperazinedihydrochloride salt, 3 mL of ethanol was heated to 70° C. into asolution. To this solution were added sequentially 383 mg of sodiumiodide and 250 mg of 4-(methylsulfonyl)benzyl bromide, followed bystirring at 70° C. for 14 hours. After the solution was cooled to roomtemperature, ethanol was removed under reduced pressure and 20 mL ofaqueous 2N sodium hydroxide was added and the mixture was extracted with20 mL×2 of ethyl acetate. The organic layers were combined, washed with20 mL of aqueous saturated sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated to give 176 mg of1-[4-(methylsulfonyl)benzyl]homopiperazine.

The resulting 1-[4-(methylsulfonyl)benzyl]homopiperazine was dissolvedin 5 mL of dichloromethane, followed by adding 223 mg ofdiphenylacetaldehyde and 217 mg of sodium triacetoxyborohydride. Afterthe mixture was stirred at room temperature for 16 hours, it was mixedwith 30 mL of aqueous saturated sodium hydrogencarbonate, and extractedwith 30 mL×2 of ethyl acetate. The organic layers were combined, washedwith 30 mL of saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, concentrated, and purified by columnchromatography (silica gel, ethyl acetate) to obtain 173 mg of thetitled compound. This was treated with a hydrogen chloride solution inether and the solvent was removed under reduced pressure, the residuewas dried to give the hydrochloride salt of the titled compound.

Compound No. 6 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.64-1.77 (m, 2H), 2.51-2.64 (m, 4H), 2.67-2.83 (m, 4H), 3.04 (S,3H), 3.15 (d, J=7.6 Hz, 2H), 3.61 (s, 2H), 4.14 (t, J=7.6 Hz, 1H),7.13-7.35 (m, 10H), 7.45 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H).

Example 9 Preparation of1-(3-Hydroxy-3,3-diphenylpropyl)-4-(4-chlorobenzyl)homopiperazine(Compound No. 107)

A solution of 54 mg of methyl ³-[4-(4-chlorobenzyl)homopiperazinyl]propionate in 10 mL of ether was mixed with undernitrogen, 4 mL of 1 M phenyl magnesium bromide. The mixture was stirredat room temperature for 30 minutes, mixed with aqueous saturatedammonium chloride and the mixture was extracted with 50 mL of ethylacetate. The extract was washed with 50 mL of saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered, concentrated,and purified by column chromatography (silica gel, ethylacetate/methanol 9:1) to give 65 mg of the titled compound. This wastreated with a hydrogen chloride solution in ether and the solvent wasremoved under reduced pressure and the residue was dried to give thehydrochloride salt of the titled compound.

Compound 107 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.77-1.86 (m, 2H), 2.36-2.40 (m, 2H), 2.54-2.71 (m, 10H), 3.58(s, 2H), 7.15-7.20 (m, 2H), 7.26-7.32 (m, 8H), 7.44-7.48 (m, 4H).

Example 10 Preparation of1-(3,3-Diphenylpropyl)-4-(4-carbamoylbenzyl)homopiperazine (Compound No.55)

A 20 mL solution of 175 mg of compound No. 30 in 20 mL of t-butylalcohol was mixed with 570 mg of ground potassium hydroxide and themixture was refluxed for 2.5 hours. The solution was cooled to roomtemperature and mixed with 50 mL of water and 100 mL of ethyl acetate.The organic layer was separated and the aqueous layer was extracted with50 mL of ethyl acetate. The organic layers were combined, dried overanhydrous sodium sulfate, filtered, concentrated, and purified by columnchromatography (silica gel, ethyl acetate/methanol 4:1) to give 91 mg ofthe titled compound. This was treated with a hydrogen chloride solutionin ether and the solvent was removed under reduced pressure and theresidue was dried to give the hydrochloride salt of the titled compound.

Compound No. 55 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 0.86-0.91 (m, 1H), 1.23-1.28 (m, 2H), 1.73-1.82 (m, 2H),2.18-2.26 (m, 2H), 2.42-2.47 (m, 2H), 2.65-2.73 (m, 6H), 3.67 (s, 2H),5.6-6.2 (brs, 2H), 7.13-7.30 (m, 10H), 7.41 (d, 2H, J=8.25 Hz), 7.75 (d,2H, J=8.25 Hz).

Example 11 Preparation of1-[3,3-Di(2-furyl)-3-hydroxypropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 129)

To a solution of 2-furyl lithium prepared in 50 mL of THF using 3 mL offuran and 2 mL of 1.63 M n-butyllithium was added dropwise at 0° C., a10 ml solution in THF of 99 mg of methyl3-[4-{4-(methylsulfonyl)benzyl}homopiperazinyl]propionate. Afterstirring at 0° C. for 1 hour, the mixture was mixed with 50 mL of anaqueous saturated ammonium chloride, and extracted with 50 mL×2 of ethylacetate. The extracts were combined, dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by column chromatography(silica gel, ethyl acetate) to give 62 mg of the titled compound.

Compound No. 129 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm):1.80-1.89 (m, 2H), 2.32-2.36 (m, 2H), 2.56-2.60 (m, 2H), 2.74-2.78 (m,2H), 2.66-2.70 (m, 6H), 3.05 (s, 3H), 3,70 (s, 2H), 6.30-6.34 (m, 4H),7.36-7.37 (m, 2H), 7.55 (d, 2H J=8.25 Hz), 7.86 (d, 2H, J=8.25 Hz).

Example 12 Preparation of1-[3,3-bis(4-Hydroxyphenyl)-3-hydroxypropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 119)

To a 2.0 mL anhydrous THF solution of 120 mg of methyl3-[4-(4-chlorobenzyl)homopiperazinyl]propionate was added undernitrogen, 2.0 mL solution in THF of 1.5 mmol of4-(tert-butyldimethylsilyloxy)phenyl magnesium bromide. The mixture wasstirred at room temperature for 30 minutes and an aqueous saturatedammonium chloride solution was added and the mixture was extracted with20 mL×3 of ethyl acetate. The extracts were washed with aqueoussaturated sodium chloride, dried over anhydrous sodium sulfate,filtered, concentrated, and purified by column chromatography (silicagel, hexane/ethyl acetate 1:1) to give 33 mg of a silyl protected formof the titled compound. The resulting oily product was dissolved in 3 mLof THF and mixed with 0.8 mL of a 1N THF solution of tributylammoniumfluoride. The mixture was stirred at room temperature for 4 hours, mixedwith aqueous saturated ammonium chloride and extracted with 20 mL×3 ofethyl acetate. The extracts were washed with aqueous saturated sodiumchloride, dried over anhydrous sodium sulfate, filtered, concentrated,and purified by column chromatography to obtain 5 mg of the titledcompound.

Compound No. 119 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm):1.81-1.94 (m, 2H), 2.35 (broad s, 3H), 2.55-2.82 (m, 1H), 3.08 (s, 3H),3.70 (s, 2H), 6.67 (d, J=8.6 Hz, 4H), 7.14 (d, J=8.9 Hz, 4H), 7.48 (d,J=8.3 Hz, 2H), 7.81 (d, J=8.3 Hz, 2H).

Example 13 Preparation of1-[3-Hydroxy-3-(1-methyl-2-pyrrolyl)-3-phenylpropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 136)

1.0 mL of an anhydrous THF solution of 121 mg of methyl3-[4-{4-(methylsulfonyl)benzyl}homopiperazinyl]propionate was addedunder nitrogen to 6 mL of a THF solution of 1.5 mmol of1-methyl-2-pyrrolyl cerium dichloride at −78° C. After stirring at −78°C. for 3 hours, the mixture was mixed with 20 mL of water and it wasfiltered from insoluble matter using Celite, followed by extracting thefiltrate with 30 mL×2 of ethyl acetate. The extracts were dried overanhydrous sodium sulfate, filtered, concentrated, and purified by columnchromatography (silica gel, ethyl acetate, ethyl acetate/methanol 10:1)to give 7 mg of the titled compound.

Compound No. 136 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.88(d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.32-7.16 (m, 5H), 6.48-6.47(m, 1H), 6.22-6.20 (m, 1H), 6.06-6.04 (m, 1H), 3.72 (s, 2H), 3.26 (s,3H), 3.06 (s, 3H), 2.87-2.39 (m, 11H), 2.05-1.83 (m, 3H).

Example 14 Preparation of1-[3,3-bis(1-methyl-2-pyrrolyl)-3-hydroxypropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 127)

2.0 mL of an anhydrous THF solution of 160 mg of1-[4-(methylsulfonyl)benzyl]-4-(3-oxo-3-phenylpropyl)homopiperazine wasadded under nitrogen at −78° C. to a 3 mL THF solution of 0.8 mmol of1-methyl-2-pyrrolylcerium dichloride. The mixture was stirred at −78° C.for 3 hours and then it was mixed with 20 mL of water and filtered frominsolubles, using Celite; the filtrate was extracted with 30 mL×2 ofethyl acetate. The extracts were dried over anhydrous sodium sulfate,filtered, concentrated, and purified by column chromatography (silicagel, hexane/ethyl acetate 1:3, ethyl acetate) to give 18 mg of thetitled compound.

Compound No. 127 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.88(d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 6.50-6.48 (m, 2H), 6.24-6.22(m, 2H), 6.03-6.00 (m, 2H), 3.71 (s, 2H), 3.21 (s, 6H), 3.05 (s, 3H),2.8-2.62 (m, 10H), 2.36-2.32 (m, 2H), 1.88-1.83 (m, 2H).

Example 15 Preparation of1-(3,5-Difluorophenyl)-3-hydroxy-3-(3-hydroxyphenyl)propyl-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 138)

To 1.0 mL anhydrous THF solution of 263 mg of1-[4-(methylsulfonyl)benzyl]-4-[3-oxo-3-{3-(tert-butyldimethylsilyloxy)phenyl}propyl]homopiperazinewas added 3 mL of a THF solution of 2.5 mmol of3,5-difluorophenylmagnesium bromide under nitrogen at 0° C. The mixturewas stirred at room temperature for 3 hours, and aqueous saturatedammonium chloride was added and the mixture was extracted with 40 mL×2with ethyl acetate. The extracts were combined, dried over anhydroussodium sulfate, filtered, concentrated, and purified by columnchromatography (silica gel, ethyl acetate, ethyl acetate/methanol 10:1)to obtain 11 mg of a silyl protected form of the titled compound.

The resulting oil was dissolved in 5 mL of THF and mixed with 0.07 mL ofa THF solution of 1 M tetrabutylammonium fluoride. The mixture wasstirred at room temperature for 30 minutes and mixed with 20 mL of waterand extracted with 30 mL×3 of ethyl acetate. The extracts were combined,dried over anhydrous sodium sulfate, filtered, concentrated, andpurified by column chromatography (silica gel, ethyl acetate) to give 11mg of the titled compound.

Compound No. 138 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.88(d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.18 (t, J=7.9 Hz, 1H),7.02-6.93 (m, 4H), 6.70-6.58 (m, 1H), 3,68 (s, 2H), 3,06 (s, 3H),2.72-2.60 (m, 10H), 2.33-2.28 (m, 2H), 1.85-1.76 (m, 2H).

Example 16 Preparation of1-(3-(4-Hydroxyphenyl)-3-phenylpropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 42)

5.0 mL solution in dichloromethane of 33 mg of1-[3-(4-methoxyphenyl)3-phenylpropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine was cooled undernitrogen to −78° C. followed by adding 0.022 mL of boron tribromide. Themixture was gradually allowed to rise to room temperature, at whichtemperature the mixture was stirred for 3 hours, followed by adding 3 mLof an aqueous saturated sodium hydrogencarbonate solution and extractingwith a 50 mL×2 of ethyl acetate. The extracts were combined, dried overanhydrous sodium sulfate, filtered, concentrated, and purified by columnchromatography (silica gel, ethyl acetate/methanol 9:1) to obtain 12 mgof the titled compound. This was treated with a hydrogen chloridesolution in ether and the solvent was removed under reduced pressure andresidue was dried to give the hydrochloride salt of the titled compound.

Compound No. 42 (free base) had the following ¹H NMR (CDCl₃, 270 MHz) δ(ppm): 1.75-1.8 (m, 2H), 2.15-2.3 (m, 2H), 2.4-2.9 (m, 10H), 3.04 (s,3H), 3.68 (s, 2H), 3.82 (t, J=7.5 Hz, 1H), 6.59 (d, J=8.6 Hz, 2H),7.1-7.3 (m, 5H), 7.51 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.2 Hz, 2H).

Example 17 Preparation of1-[3-Hydroxy-3-(3-methylainophenyl)-3-phenylpropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 146)

To a solution of 34 mg of compound No. 143 in 1.2 mL of acetonitrile and0.3 mL of water was added 14 mg of RhCl(PPh₃)₃, and the mixture wasstirred at 100° C. for 2 days, After the mixture was allowed to cool toroom temperature, evaporation of acetonitrile and column chromatography(silica gel, ethyl acetate) gave 9.0 mg of the titled compound.

Compound No. 146 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm):1.79-1.91 (m, 2H), 2.34-2.41 (m, 2H), 2.55-2.75 (m, 11H), 2.80 (s, 3H),3.05 (s, 3H), 3.70 (s, 2H), 5.40 (broad s, 1H), 6.39-6.44 (m, 1H),6.70-6.80 (m, 2H), 7.05-7.20 (m, 2H), 7.21-7.31 (m, 3H), 7.41-7.48 (m,2H), 7.55 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).

Example 18 Preparation of1-[3-(3-Acetylaminophenyl)-3-hydroxy-3-phenylpropyl]-4-[4-(methylsulfonyl)benzyl]homopiperazine(Compound No. 162)

To a solution of 352 mg of compound No. 159 in 5 mL of dichloromethanewas added 190 μL of triethylamine and 130 μL of acetic anhydride. Themixture was stirred at room temperature for 2 hours. 3 mL of water wasadded and the mixture was extracted with dichloromethane. The extractwas concentrated and purified by column chromatography (silica gel,ethyl acetate/methanol 7:3) to give 224 mg of the titled compound as awhite solid.

Compound No. 162 had the following ¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.88(d, J=8.3 Hz, 2H), 7.57-7.45 (m, 5H), 7.22-7.16 (m, 6H), 3.70 (s, 2H),3.05 (s, 3H), 2.73-2.60 (m, 10H), 2.40-2.37 (m, 2H), 1.88-1.81 (m, 2H).

Examples 19-151

The compounds of this invention were synthesized pursuant to methods ofExample 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 14, 15, or 16, using thecorresponding reactant respectively. The ¹H NMR data, yields, andsynthetic methods are summarized in Table 2.

TABLE 2 Compound ¹H NMR Data Yield Synthetic No. (CDCl₃) δ(ppm) (%)method Example 19 5 1.69-1.82(m, 2H), 2.58-2.70(m, 4H), 2.69(t, J=5.9Hz,2H), 2.76(t, 47 Similar to J=5.9Hz, 2H), 3.04(s, 3H), 3.73(s, 2H),4.61(s, 1H), 7.11-7.21(m, 2H), Example 2 7.26(dd, J=7.3, 7.3Hz, 4H),7.42(d, J= 7.3Hz, 4H), 7.56(d, J=8.6Hz, 2H), 7.87(d, J=8.6Hz, 2H).Example 20 7 2.15-2.35(m, 4H), 2.35-2.60(m, 8H), 3.04(s, 3H), 3.57(s,2H), 3.97(t, 44 Similar to J=7.3Hz, 1H), 7.10-7.34(m, 10H), 7.53(d,J=8.3Hz, 2H), 7.88(d, Example 1 J=8.3Hz, 2H), Example 21 8 2.15-2.33(m,4H), 2.33-2.55(m, 8H), 3.45(s, 2H), 3.96(t, J=6.9Hz, 1H), 54 Similar to7.10-7.33(m, 14H). Example 1 Example 22 16 1.78-1.88(m, 2H),2.18-2.27(m, 2H), 2.42-2.49(m, 2H), 2.66-2.74(m, 4H), 33 Similar to2.78-2.87(m, 4H), 3.26(s, 2H), 4.03(t, J=7.6Hz, 1H), 7.07-7.37(m, 13H),Example 1 7.57(d, J=7.6Hz, 2H), 9.31(br.s, 1H). Example 23 171.61-1.71(m, 2H), 2.14-2.23(m, 2H), 2.35-2.41(m, 2H), 2.45-2.65(m, 10H),21 Similar to 2.93(t, J=5.3Hz, 2H), 3.99(t, J=7.6Hz, 1H), 5.30(s, 1H),7.13-7.31(m, Example 1 10H), 7.46(d, J=8.6Hz, 2H), 7.80(d, J=8.6Hz, 2H).Example 24 18 1.67-1.77 (m, 2H), 2.12-2.24(m, 2H), 2.35-2.41(m, 2H),2.55-2.64(m, 4H), 43 Similar to 2.69-2.77 (m, 4H), 3.19(s, 2H), 3.98(t,J=7.6Hz, 1H), 4.47(d, J=5.9Hz, Example 1 2H), 7.13-7.35(m, 10H),7.63(br, 1H), Example 25 19 1.76-1.85(m, 2H), 2.19-2.28(m, 2H),2.41-2.48(m, 2H), 2.65-2.75(m, 4H), 51 Similar to 2.81-2.87(m, 4H),2.96(t, J=5.9Hz, 2H), 4.00(t, J=7.6Hz, 1H), Example 1 4.06(t, J=5.9Hz,2H), 6.88-6.97(m, 3H), 7.12-7.21(m, 2H), 7.21-7.31(m, 10H). Example 2620 1.68-1.78(m, 2H), 2.16-2.25(m, 2H), 2.36-2.43(m, 2H), 2.55-2.71(m,10H), 13 Similar to 3.28(dt, J=5.9, 5.0Hz, 2H), 3.97(t, J=7.6Hz, 1H),5.55(br, 1H), Example 1 6.99-7.05(m, 1H), 7.13(d, J=7.34Hz, 15H).Example 27 21 1.82-1.93(m, 2H), 2.19-2.28(m, 2H), 2.43-2.50(m, 2H),2.68-2.81(m, 10H), 19 Similar to 3.52(dt, J=5.6. 5.0Hz, 2H), 3.99(t,J=7.6Hz, 1H), 7.08(br, 1H), Example 1 7.14-7.31(m, 10H), 7.38-7.52(m,3H), 7.81(d, J=6.6Hz, 2H). Example 28 22 1.78-1.87(m, 2H), 2.21-2.30(m,2H), 2.43-2.50(m, 2H), 2.68-2.74(m, 4H), 25 Similar to 2.81-2.88(m, 4H),3.44(s, 2H), 3.99(t, J=7.6Hz, 1H), 5.14(s, 2H), Example 1 7.12-7.40(m,15H). Example 29 24 1.73-1.83(m, 2H), 2.17-2.26(m, 2H), 2.41-2.47(m,2H), 2.63-2.73(m, 8H), 50 Similar to 3.72(s, 2H), 4.02(t, J=7.6Hz, 1H),7.12-7.20(m, 2H), 7.20-7.31(m, 8H), Example 1 7.46(dd, J=7.9, 7.9Hz,1H), 7.67(d, J=7.9Hz, 2H), 8.09(dd, J=7.9, 1.0Hz, 1H), 8.21(s, 1H).Example 30 25 1.70-1.74(m, 2H), 2.16-2.21(m, 2H), 2.37-2.41(m, 2H),2.54-2.57(m, 2H). 58 Similar to 2.59-2.66(m, 6H), 3.89(s, 2H), 4.01(t,J=7.7Hz, 1H). 7.13-7.17(m, 2H). Example 1 7.23-7.28(m, 8H), 7.34-7.37(m,1H), 7.48-7.51(m, 1H), 7.56(d, J=7.7Hz, 1H), 7.76(dd, J=8.1, 1.1Hz, 1H).Example 31 26 1.73-1.80(m, 2H), 2.18-2.25(m, 2H), 2.41-2.45(m, 2H),2.64-2.71(m, 8H), 31 Similar to 3.57(s, 2H), 3.79(s, 3H), 4.00(t,J=7.8Hz, 1H), 6.84(d, J=8.8Hz, Example 1 2H), 7.13-7.18(m, 2H),7.21-7.28(m, 10H). Example 32 26 1.74-1.80(m, 2H), 2.18-2.24(m, 2H),2.40-2.45(m, 2H), 2.62-2.71(m, 8H), 37 Similar to 3.61(s, 2H), 3.80(s,3H), 4.01(t, J=7.8Hz, 1H), 6.77(dd, J=8.3, Example 1 2.4Hz, 1H),6.88-6.91(m, 2H), 7.13-7.19(m, 2H), 7.20-7.29(m, 9H). Example 33 281.78-1.87(m, 2H), 2.19-2.27(m, 2H), 2.39-2.48(m, 2H), 2.63-2.81(m, 8H),43 Similar to 3.71(s, 2H), 3.81(s, 3H), 4.01(t, J=7.8Hz, 1H), 6.85(d,J=7.8Hz, 1H), Example 1 6.93(dd, J=7.3, 7.3Hz, 1H), 7.13-7.18(m, 2H),7.19-7.29(m, 9H), 7.40(d, J=7.8Hz, 1H). Example 34 29 1.87-1.94(m, 2H),2.17-2.25(m, 2H), 2.37-2.42(m, 2H), 2.60-2.65(m, 2H), 45 Similar to2.70-2.75(m, 2H), 3.28-3.34(m, 2H), 3.35-3.40(m, 2H), 3.99(t, J=7.8Hz,Example 1 1H), 6.77(ddd, J=8.3, 6.8, 1.0Hz, 1H), 7.02(dd, J=8.8, 1.0Hz,1H), 7.14-7.19(m, 2H), 7.20-7.29(m, 8H), 7.35(ddd, J=8.8, 6.8, 1.5Hz,1H), 7.71(dd, J=8.3, 1.5Hz, 1H). Example 35 30 1.7-1.85(m, 2H),2.15-2.3(m, 2H), 2.4-2.5(m, 2H), 2.6-2.75(m, 8H), 3.67(s, 38 Similar to2H), 4.01(t, J=7.5Hz, 1H), 7.1-7.35(m, 10H), 7.44(d, J=8.3Hz, Example 12H), 7.59(d, J=8.3Hz, 2H). Example 36 31 1.7-1.85(m, 2H), 2.15-2.3(m,2H), 2.4-2.5(m, 2H), 2.6-2.75(m, 8H), 30 Similar to 3.66(s, 2H), 4.01(t,J=7.5Hz, 1H), 7.1-7.35(m, 10H), 7.43(d, J=8.0Hz, Example 1 2H), 7.55(d,J=8.0Hz, 2H). Example 37 32 1.75-1.88(m, 2H), 2.20-2.32(m, 2H),2.39-2.50(m, 2H), 2.62-2.90(m, 12H), 53 Similar to 4.00(t, J=7.6Hz, 1H),7.11-7.25(m, 10H), 7.34(d, J=8.6Hz, 2H), Example 1 8.13(d, J=8.6Hz, 2H).Example 38 33 1.73-1.89(m, 4H), 2.16-2.27(m, 2H), 2.39-2.47(m, 2H),2.48(t, J=7.3Hz, 55 Similar to 2H), 2.58-2.70(m, 8H), 2.73(t, J=7.3Hz,2H), 4.00(t, J=7.6Hz, 1H), Example 1 7.12-7.20(m, 2H), 7.20-7.30(m, 8H),7.33(d, J=8.6Hz, 2H), 8.13(d, J=8.6Hz, 2H), Example 39 34 1.75-1.85(m,2H), 2.2-2.35(m, 2H), 2.45-2.55(m, 2H), 2.6-2.8(m, 8H), 3.58(s, 26Similar to 2H), 3.99(t, J=7.5Hz, 1H), 7.1-7.35(m, 14H). Example 1Example 40 35 1.7-1.85(m, 2H), 2.15-2.3(m, 2H), 2.4-2.5(m, 2H),2.6-2.75(m, 8H), 3.66(s, 48 Similar to 2H), 3.95(s, 3H), 4.02(t,J=7.5Hz, 1H), 6.96(d, J=6.9Hz, 1H), Example 1 7.1-7.35(m, 11H), 7.81(d,J= 8.2Hz, 1H). Example 41 36 1.73-1.86(m, 2H), 2.15-2.29(m, 2H),2.40-2.51(m, 2H), 2.55-2.71(m, 8H), 57 Similar to 3.04(s, 3H), 3.71(s,2H), 4.01(t, J=7.6Hz, 1H), 7.11-7.32(m, 10H), Example 1 7.54(d, J=8.2Hz,2H), 7.87(d, J=8.2Hz, 2H). Example 42 37 1.72-1.84(m, 2H), 2.16-2.28(m,2H), 2.39-2.48(m, 2H), 2.61-2.74(m, 8H), 37 Similar to 3.74(s, 2H),3.90(s, 3H), 4.01(t, J=7.6Hz, 1H), 7.11-7.20(m, 2H), Example 17.20-7.31(m, 8H), 7.40(d, J=8.3Hz, 2H), 7.97(d, J=8.3Hz, 2H). Example 4338 1.7-1.75(m, 2H), 2.15-2.25(m, 2H), 2.29(s, 3H), 2.4-2.5(m, 2H), 10Similar to 2.6-2.77(m, 8H), 3.05(s, 3H), 3.70(s, 2H), 3.97(t, J=7.6Hz,1H), 7.03-7.33(m, Example 1 9H), 7.54(d, J=8.2Hz, 2H), 7.86(d, J=8.2Hz,2H). Example 44 39 1.7-1.75(m, 2H), 2.15-2.25(m, 2H), 2.30(s, 3H),2.4-2.5(m, 2H), 26 Similar to 2.6-2.8(m, 8H), 3.04(s, 3H), 3.70(s, 2H),3.96(t, J=7.6 Hz, 1H), 6.9-7.3(m, Example 1 9H), 7.54(d, J=8.2Hz, 2H),7.86(d, J=8.2Hz, 2H). Example 45 40 1.75-1.88(m, 2H), 2.12-2.22(m, 2H),2.28(s, 3H), 2.4-2.6(m, 2H), 26 Similar to 2.6-2.85(m, 8H), 3.05(s, 3H),3.71(s, 2H), 4.23(t, J=7.6Hz, 1H), Example 1 7.1-7.3(m, 8H), 7.35(d,J=7.5Hz, 1H), 7.54(d, J=8.2Hz, 2H), 7.88(d, J=8.2Hz 2H). Example 46 411.7-1.85(m, 2H), 2.1-2.25(m, 2H), 2.35-2.5(m, 2H), 2.55-2.75(m, 8H),3.05(s, 19 Similar to 3H), 3.71(s, 2H), 3.76(s, 3H), 3.95(t, J=7.7Hz,1H), 6.81(d, Example 1 J=8.6Hz, 1H), 7.1-7.3(m, 7H), 7.54(d, J=8.2Hz,2H), 7.87(d, J=8.2Hz, 2H). Example 47 43 1.75-1.85(m, 2H), 2.13-2.15(m,2H), 2.41(t, J=7.3Hz, 2H), 2.58-2.74(m, 40 Similar to 8H), 3.05(s, 3H),3.70(s, 2H), 4.00(t, J=7.7Hz, 1H), 7.12-7.31(m, 9H), Example 1 7.54(d,J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H). Example 48 44 1.7-1.85(m, 2H),2.12-2.25(m, 2H), 2.44(t, J=7Hz, 2H), 2.55-2.75(m, 8H), 15 Similar to3.58(s, 2H), 3.76(s, 3H), 3.95(t, J=7.7Hz, 1H), 6.81(d, J=8.8Hz, Example1 2H), 7.15(d, J=8.7Hz, 2H), 7.15-7.31(m, 9H). Example 49 451.74-1.84(m, 2H), 2.12-2.23(m, 2H), 2.37-2.45(m, 2H), 2.60-2.71(m, 8H),35 Similar to 3.02(s, 3H), 3.70(s, 2H), 4.03(t, J=7.6Hz, 1H), 6.85(dt,J=6.6, Example 1 1.5Hz, 1H), 6.94(td, J=10.2, 1.6Hz, 1H), 7.02(d,J=7.6Hz, 1H), 7.14-7.31(m, 6H), 7.54(d, J=8.6Hz, 2H), 7.87(d, J=8.2Hz,2H). Example 50 46 1.72-1.88(m, 2H), 2.15-2.30(m, 2H), 2.40-2.60(m, 2H),2.60-2.90(m, 8H), 39 Similar to 3.55(s, 2H), 3.78(t, 1H, J=7.6Hz),6.53(d, 2H, J=8.5Hz), 6.98(d, Example 16 2H, J=8.5Hz), 7.1-7.3(m, 9H).Example 51 47 1.75-1.85(m, 2H), 2.12-2.21(m, 2H), 2.39-2.45(m, 2H),2.65-2.77(m, 8H), 36 Similar to 3.04(s, 3H), 3.70(s, 2H), 4.01(t,J=7.6Hz, 1H), 6.90-6.98(m, 4H), Example 1 7.12-7.26(m, 4H), 7.54(d,J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H). Example 52 48 1.75-1.85(m, 2H),2.18-2.26(m, 2H), 2.42-2.52(m, 2H), 2.62-2.76(m, 8H), 19 Similar to3.04(s, 3H), 3.75(s, 2H), 4.01(t, J=7.6Hz, 1H), 6.91-6.99(m, 2H),Example 1 7.13-7.31(m, 7H), 7.54(d, J=8.6Hz, 2H), 7.87(d, J=8.2Hz, 2H).Example 53 49 1.74-1.85(m, 2H), 2.17-2.28(m, 2H), 2.43-2.52(m, 2H),2.63-2.72(m, 8H), 45 Similar to 3.05(s, 3H), 3.71(s, 2H), 4.38(t,J=7.6Hz, 1H), 6.94-7.21(m, 4H), Example 1 7.25-7.31(m, 5H), 7.54(d,J=8.6Hz, 2H), 7.87(d, J=8.2Hz, 2H). Example 54 50 1.72-1.85(m, 2H),2.14-2.28(m, 2H), 2.44(t, J=7.3Hz, 2H), 2.60-2.76(m, 14 Similar to 8H),3.55(s, 2H), 4.00(t, J=7.7Hz, 1H), 7.10-7.31(m, 13H). Example 1 Example55 51 1.74-1.85(m, 2H), 2.15-2.25(m, 2H), 2.43-2.52(m, 2H), 2.60-2.75(m,8H), 8 Similar to 3.03(s, 3H), 3.71(s, 2H), 4.60(t, J=7.8Hz, 1H),7.06-7.39(m, 9H), Example 1 7.54(d, J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H).Example 56 52 1.69-1.77(m, 2H), 2.15-2.30(m, 2H), 2.37-2.45(m, 2H),2.60-2.69(m, 8H), 21 Similar to 3.57(s, 2H), 4.00(t, J=7.7Hz, 1H),6.97(t, J_(N-F)=8.9Hz, 2H), Example 1 7.11-7.18(m, 2H), 7.21-7.30(m,10H). Example 57 53 1.71-1.79(m, 2H), 2.10-2.20(m, 2H), 2.33-2.40(m,2H), 2.57-2.69(m, 8H), 23 Similar to 3.57(s, 2H), 3.99(t, J=7.8Hz, 1H),7.10-7.15(m, 4H), 7.20-7.25(m, 8H), Example 1 Example 58 54 1.70-1.79(m,2H), 2.11-2.17(m, 2H), 2.33-2.41(m, 2H), 2.60-2.68(m, 8H), 15 Similar to3.58(s, 2H), 4.00(t, J=7.7Hz, 1H), 6.90-6.99(m, 4H), 7.12-7.20(m, 4H),Example 1 7.26(s, 4H). Example 59 56 1.86-1.93(m, 2H), 2.25-2.37(m, 2H),2.54-2.60(m, 2H), 2.67-2.95(m, 8H), 10 Similar to 3.05(s, 3H), 3.71(s,2H), 4.00(t, J=7.9Hz, 1H), 7.11-7.19(m, 4H), Example 1 7.20-7.30(m, 4H),7.53(d, J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H). Example 60 57 1.73-1.86(m,2H), 2.22-2.31(m, 2H), 2.43-2.52(m, 2H), 2.65-2.80(m, 8H), 29 Similar to3.55(s, 2H), 3.91(t, J=7.6Hz, 1H), 6.3(broad s,1H), 6.61(d, J=8.2Hz,Example 1 2H), 7.08-7.32(m, 12H). Example 61 58 1.70-1.85(m, 2H),2.15-2.28(m, 2H), 2.40-2.54(m, 2H), 2.57-2.80(m, 8H), 48 Similar to3.05(S, 3H), 3.69(s, 2H), 3.90(t, J=7.3Hz, 1H), 6.60-6.68(m, 2H),Example 1 6.80(d, J=7.9Hz, 1H), 7.08-7.32(m, 6H), 7.52(d, J=8.2Hz, 2HJ.7.87(d, J=8.2Hz, 2H). Example 62 59 1.90-2.10(m, 2H), 2.40-2.97(m, 12H),3.05(S, 3H), 3.75(s, 2H), 44 Similar to 4.40-4.50(m, 1H), 6.65-6.77(m,2H), 6.93(d, J=7.6Hz, 1H), 7.00-7.10(m, 1H), Example 1 7.15-7.35(m, 5H),7.60(d, J=8.3Hz, 2H), 7.89(d, J=8.3Hz, 2H). Example 63 60 1.73-1.79(m,2H), 2.15-2.26(m, 2H), 2.37-2.47(m, 2H), 2.60-2.75(m, 8H), 29 Similar to2.98(broad s, 3H), 3.10(broad s, 3H), 3.64(s, 2H), 4.00(t, J=7.6Hz,Example 1 1H), 7.15-7.33(m, 10H), 7.35(s, 4H). Example 64 611.70-1.76(m, 2H), 2.10-2.24(m, 2H), 2.35-2.45(m, 2H), 2.58-2.70(m, 8H),10 Similar to 3.64(s, 2H), 3.97(t, J=7.6Hz, 1H), 4.90(broad s, 2H),7.10-7.30(m, Example 1 10H), 7.42(d, J=8.1Hz, 2H), 7.82(d, J=8.1Hz, 2H).Example 65 62 7.54(d, J=8.1Hz, 4H), 7.34(d, J=8.1Hz, 4H), 7.26(s, 4H),4.20(t, 72 Similar to J=7.6Hz, 1H), 3.58(s, 2H), 2.69-2.61(m, 8H),2.42-2.37(m, 2H), 2.25-2.17(m, Example 1 2H), 1.81-1.72(m, 2H). Example66 63 1.65-1.80(m, 2H), 2.10-2.25(m, 2H), 2.40-2.51(m, 2H), 2.51-2.74(m,8H), 19 Similar to 3.53(s, 2H), 3.84(t, J=7.6Hz, 1H), 6.53(s, 1H),6.60(dd, J=1.6, Example 1 7.9Hz, 1H), 6.76(d, J=7.6Hz, 1H), 7.06-7.33(m,10H). Example 67 64 1.85-2.10(m, 2H), 2.30-2.90(m, 12H), 3.61(s, 2H),4.40-4.50(m, 1H), 39 Similar to 6.64-6.75(m, 2H), 6.93(d, J=7.9Hz, 1H),7.00-7.10(m, 1H), 7.15-7.40(m, 9H). Example 1 Example 68 65 1.72-1.81(m,2H), 2.10-2.19(m, 2H), 2.42-2.45(m 2H), 2.64-2.72(m, 8H), 49 Similar to3.58(s, 2H), 3.76(s, 6H), 6.80(d, 4H. J=8.91Hz), 7.13(d, 4H, J=8.91Hz),Example 1 7.26(s, 4H). Example 69 66 1.83-1.85(m, 2H), 2.16-2.24(m, 2H),2.59-2.72(m, 6H), 2.84-2.94(m, 4H), 19 Similar to 3.62(s, 2H), 3.76(m,1H), 6.69(d, 4H, J=8.58Hz), 7.05(d, 4H, J=8.58Hz), Example 1 7.30(s,4H). Example 70 67 1.81-1.85(m, 2H), 2.15-2.24(m, 2H), 2.56-2.62(m, 2H),2.68-2.72(m, 4H), 3 Similar to 2.81-2.91(m, 4H), 3.10(s, 3H),3.73-3.78(m, 3H), 6.68(d, 4H, J=8.58Hz), Example 1 7.05(d, 4H,J=8.58Hz), 7.59(d, 2H, J=8.58Hz), 7.89(d, 2H, J=8.58Hz). Example 71 681.74-1.80(m, 2H), 1.90(broad s, 2H), 2.12-2.28(m, 2H), 2.40-2.76(m,10H), 1 Similar to 2.91(s, 3H), 3.49(s 2H), 6.84-6.88(m, 1H),7.00-7.20(m, 6H), Example 1 7.30-7.35(m, 2H), 7.43(d, J=8.4Hz, 2H),7.74(d, J=8.4Hz, 2H). Example 72 102 1.38-1.52(m, 2H), 1.72-1.86(m, 2H),1.98-2.12(m, 2H), 2.52(t, J=7.6Hz, 59 Similar to 2H), 2.58-2.75(m, 8H),3.05(S, 3H), 3.69(s, 2H), 3.89(t, J=7.9Hz, Example 1 1H), 7.11-7.31(m,10H), 7.53(d, J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H). Example 73 1031.71-1.77(m, 2H), 2.33-2.39(m, 2H), 2.49-2.55(m, 2H), 2.57-2.71(m, 8H),4 Similar to 3.05(s, 3H), 3.07(s, 3H), 3.67(s, 2H), 7.15-7.36(m, 10H),7.52(d, Example 1 J=8.3Hz, 4H), 7.86(d, J=8.3Hz, 2H). Example 74 1041.63-1.80(m, 2H), 2.10-2.20(m, 2H), 2.35-2.75(m, 13H), 3.01(s, 3H), 20Similar to 3.05(s, 3H), 3.61(s, 2H), 6.55-6.67(m, 4H), 6.80-6.90(m, 2H),7.03-7.13(m, Example 1 2H), 7.46(d, J=8.1Hz, 2H), 7.84(d, J=8.1Hz, 2H).Example 75 106 1.79-1.88(m, 2H), 2.37-2.41(m, 2H), 2.56-2.71(m, 10H),3.05(s, 3H), 69 Similar to 3.71(s, 2H), 7.15-7.20(m, 2H), 7.26-7.32(m,4H), 7.45-7.48(m, 4H), 7.56(d, Example 9 2H, J=8.25Hz), 7.88(d, 2H,J=8.58Hz). Example 76 108 1.75-1.86(m, 2H), 2.29(s, 6H), 2.32-2.36(m,2H), 2.53-2.71(m, 10H), 26 Similar to 3.57(s, 2H), 7.09(d, 2H,J=8.24Hz), 7.26(s, 4H), 7.33(d, 2H, J=8.25Hz). Example 9 Example 77 1091.57-1.61(m, 2H), 2.12-2.24(m, 2H), 2.32-2.57(m, 10H), 3.45(s, 2H), 75Similar to 4.75(broad s, 3H), 6.40-6.51(m, 2H), 6.67-6.77(m, 4H),6.88-7.00(m, 2H), Example 12 7.09-7.20(m, 4H), (solvent: CD₃OD) Example78 110 1.80-1.84(m, 2H), 2.38-2.42(m, 2H), 2.58-2.72(m, 10H), 3.58(s,2H), 84 Similar to 7.27(s, 4H), 7.54-7.62(m, 8H). Example 9 Example 79111 7.35(d, J=8.9Hz, 4H), 7.26(s, 4H), 6.82(d, J=8.9Hz, 4H), 3.76(s,6H), 38 Similar to 3.56(s, 2H), 2.70-2.53(m, 10H), 2.33-2.29(m, 2H),1.83-1.78(m, 2H). Example 9 Example 80 112 7.26(s, 4H), 7.26-7.70(m,6H), 6.36(dd, J=7.9, 2.0Hz, 2H), 3.77(s, 6H), 22 Similar to 3.57(s, 2H),2.71-2.55(m, 10H), 2.36-2.32(m, 2H), 1.83-1.79(m, 2H). Example 9 Example81 113 1.84-1.88(m, 2H), 2.46-2.48(m, 2H), 2.66-2.76(m, 10H), 3.04(s,.3H), 89 Similar to 3.72(s, 2H), 7.25-7.43(m, 6H), 7.56-7.60(m, 10H),7.88(d, 2H, J=8.58Hz). Example 9 Example 82 114 1.65-1.78(m, 2H),2.27-2.38(m, 2H), 2.45-2.68(m, 11H), 3.04(s, 3H), 52 Similar to 3.59(s,2H), 6.62(d, J=7.9Hz, 2H), 6.90-7.13(m, 6H), 7.45(d, J=8.3Hz, Example 122H), 7.81(d, J=8.3Hz, 2H). Example 83 115 7.87(d, J=8.2Hz, 2H), 7.66(d,J=7.6Hz, 2H), 7.54(d, J=8.2Hz, 2H), 83 Similar to 7.18(t, J=7.6Hz, 2H),6.97(t, J=7.6Hz, 2H), 6.78(d, J=7.7Hz, 2H), 3.69(s, Example 9 2H),3.42(s, 6H), 3.05(s, 3H), 2.78-2.50(m, 12H), 1.86-1.81(m, 2H). Example84 116 1.28(s, 18H), 1.84-1.86(m, 2H), 2.34-2.38(m, 2H), 2.54-2.72(m,10H), 83 Similar to 3.05(s, 3H), 3.71(s, 2H), 7.27-7.31(m, 4H),7.36-7.39(m, 4H), 7.56(d, 2H, Example 9 J=8.58Hz), 7.88(d, 2H,J=8.25Hz). Example 85 117 7.89(d, J=8.3Hz, 2H), 7.58-7.54(m, 10H),3.72(s, 2H), 3.05(s, 3H), 61 Similar to 2.72-2.59(m, 10H), 2.43-2.39(m,2H), 1.84-1.80(m, 2H), 1.59(br s, 1H). Example 9 Example 86 1181.80-1.90(m, 2H), 1.85(s, 6H), 2.45-2.52(m, 4H), 2.65-2.80(m, 8H), 13Similar to 3.05(s, 3H), 3.10(broad s, 1H), 3.72(s, 2H), 7.01(d, J=7.4Hz,2H), 7.13(t, Example 9 J=7.4Hz, 2H), 7.20(t, J=7.4Hz, 2H), 7.56(d,J=8.1Hz, 2H), 7.77(d, J=7.8Hz, 2H), 7.88(d, J=8.1Hz, 2H), (solvent:CDCl₃—CD₃OD). Example 87 120 1.85-1.97(m, 2H), 2.39-2.49(m, 4H),2.67-2.85(m, 9H), 2.85-2.95(m, 2H), 10 Similar to 3.04(s, 3H), 3.71(s,2H), 7.05-7.15(m, 2H), 7.18-7.27(m, 2H), Example 9 7.53-7.62(m, 4H),7.67-7.80(m, 4H), 7.88(d, J=8.3Hz, 2H), 8.17-8.31(m, 4H). Example 88 1211.75-1.89(m, 2H), 2.28-2.33(m, 2H), 2.51-2.57(m, 2H), 2.58-2.75(m, 9H),33 Similar to 2.89(s, 12H), 3.04(s, 3H), 3.70(s, 2H), 6.67(d, J=8.6Hz,4H), 7.29(d, Example 9 J=8.6Hz, 4H), 7.55(d, J=8.3Hz, 2H), 7.87(d,J=8.3Hz, 2H). Example 89 122 1.81-1.86(m, 2H), 2.26-2.30(m, 2H),2.58-2.73(m, 10H), 3.06(s, 3H), 84 Similar to 3.71(s, 2H), 5.91(s, 4H),6.72-6.75(m, 2H), 6.91-6.94(m, 4H), 7.56(d, 2H, Example 9 J=8.25Hz),7.88(d, 2H, J=8.25Hz). Example 90 123 1.73-1.81(m, 2H), 2.26-2.31(m,2H), 2.48-2.46(m, 2H), 2.56-2.78(m, 8H), 36 Similar to 3.54(s, 2H),4.40(broad s, 3H), 6.72(d, J=8.6Hz, 4H), 7.20(d, J=8.6Hz, Example 122H), 7.23-7.25(m, 4H), (solvent: CDCl₃—CD₃OD) Example 91 125 7.88(d,J=8.3Hz, 2H), 7.63-7.55(m, 3H), 7.40-7.04(m, 8H), 6.60(s, 1H), 24Similar to 3.73(s, 2H), 3.44(s, 3H), 3.05(s, 3H), 2.88-2.55(m, 11H),2.80-2.11(m, Example 14 1H), 1.92-1.85(m, 2H). Example 92 1261.78-1.91(m, 2H), 2.33-2.41(m, 2H), 2.62-2.80(m, 10H), 3.05(s, 3H), 74Similar to 3.71(s, 2H), 6.91-6.98(m, 4H), 7.19(dd, J=3.3, 3.3Hz, 2H),7.57(d, J=8.6Hz, Example 9 2H), 7.88(d, J=8.6Hz, 2H). Example 93 1281.78-1.91(m, 2H), 2.25-2.35(m, 2H), 2.55-2.78(m, 10H), 3.05(s, 3H), 19Similar to 3.71(s, 2H), 7.00(dd, J=3.3, 3.3Hz, 2H), 7.20-7.30(m, 4H),7.56(d, J=8.6Hz, Example 11 2H), 7.88(d, J=8.6Hz, 2H). Example 94 1301.80-1.96(m, 2H), 1.91(s, 6H), 2.45-2.53(m, 2H), 2.63-2.77(m, 8H), 23Similar to 2.81(t, J=5.6Hz, 2H), 3.06(s, 3H), 3.71(s, 2H), 6.77(d,J=5.3Hz, 2H), Example 9 7.06(d, J=5.3Hz, 2H), 7.56(d, J=8.3Hz, 2H),7.88(d, J=8.3Hz, 2H). Example 95 131 7.88(d, J=8.3Hz, 2H), 7.54(d,J=8.3Hz, 2H), 7.45(d, J=6.9Hz, 2H), 8 Similar to 7.31-7.13(m, 4H),7.03-6.96(m, 2H), 6.68-6.65(m, 1H), 3.69(s, 2H), 3.05(s, 3H), Example 152.74-2.58(m, 10H), 1.8(br s, 1H), 2.39-2.35(m, 2H), 1.85-1.81(m, 2H).Example 96 132 1.77-1.88(m, 2H), 2.35-2.38(m, 2H), 2.49-2.58(m, 2H),2.58-2.87(m, 10H), 30 Similar to 3.05(s, 3H), 3.68(s, 2H), 3.77(t,J=7.6Hz, 1H), 6.58-6.72(m, 6H), Example 15 7.03-7.12(m, 6H), 7.50(d,J=8.3Hz, 2H), 7.86(d, J=8.3Hz, 2H). Example 97 133 1.79-1.89(m, 2H),2.35-2.40(m, 2H), 2.55-2.76(m, 11H), 3.05(s, 3H), 30 Similar to 3.70(s,2H), 3.77(s, 3H), 6.70-6.75(m, 1H), 6.99-7.03(m, 1H), 7.13-7.31(m,Example 15 4H), 7.45-7.49(m, 2H), 7.56(d, J=8.4Hz, 2H), 7.88(d, J=8.4Hz,2H). Example 98 134 1.66-1.75(m, 2H), 2.17(s, 3H), 2.19-2.26(m, 2H),2.40-2.76(m, 11H), 21 Similar to 2.91(s, 3H), 3.49(s, 2H), 6.84-6.88(m,1H), 7.00-7.20(m, 6H), 7.30-7.35(m, Example 15 2H), 7.43(d, J=8.4Hz,2H), 7.74(d, J=8.4Hz, 2H). Example 99 135 1.79-1.88(m, 2H), 2.35-2.41(m,2H), 2.54-2.78(m, 11H), 3.03(s, 3H), 11 Similar to 3.70(s, 2H),7.10-7.48(m, 8H), 7.55(d, J=8.3Hz, 2H), 7.87(d, J=8.3Hz, Example 15 2H),Example 100 136 1.77-1.88(m, 2H), 2.35-2.40(m, 2H), 2.55-2.76(m, 11H),3.05(s, 3H), 7 Similar to 3.70(s, 2H), 3.77(s, 3H), 6.70-6.75(m, 1H),6.99-7.03(m, 1H), 7.13-7.31(m, Example 15 4H), 7.45-7.49(m, 2H), 7.56(d,J=8.4Hz, 2H), 7.88(d, J=8.4Kz, 2H). Example 101 137 7.86(d, J= 8.3Hz,2H), 7.52(d, J=8.3Hz, 2H), 7.42-7.37(m, 2H), 7.15(t, 12 Similar toJ=7.9Hz, 1H), 7.07-6.89(m, 7H), 6.69-6.65-6.47(m, 1H), 3.65(s, 2H),Example 15 3.05(s, 3H), 2.75-2.59(m, 10H), 2.39-2.32(m, 2H),1.85-1.74(m, 2H). Example 102 139 7.87(d, J=8.3Hz, 2H), 7.60-6.94(m,9H), 6.67-6.63(m, 1H), 5.75(s, 1H), 6 Similar to 4.11-3.97(m, 4H),3.68(s, 2H), 3.05(s, 3H), 2.85-2.58(m, 10H), Example 15 2.42-2.33(m,2H), 1.88-1.72(m, 2H). Example 103 140 1.65-1.78(m, 2H), 2.20-2.29(m,2H), 2.41-2.61(m, 10H), 2.77(s, 3H), 17 Similar to 2.90(s, 3H), 3.57(s,2H), 3.72-3.79(m, 2H), 4.91-5.04(m, 2H), 5.59-5.75(m, Example 15 1H),6.39-6.44(m, 1H), 6.55-6.62(m, 1H), 6.80-6.83(m, 1H), 6.96-7.08(m, 3H),7.10-7.18(m, 2H), 7.30-7.39(m, 2H), 7.43(d, J=8.2Hz, 2H), 7.76(d,J=8.2Hz, 2H). Example 104 141 1.75-1.89(m, 2H), 2.35-2.48(m, 2H),2.48-2.85(m, 11H), 3.03(s, 3H), 28 Similar to 3.46(s, 3H), 3.68(s, 2H),3.78(s, 3H), 6.36(d, J=2.3Hz, 1H), 6.53(dd, Example 15 J=8.6, 2.3Hz,1H), 7.09-7.17(m, 1H), 7.18-7.31(m, 2H), 7.35-7.45(m, 2H), 7.55(d,J=8.1Hz, 2H), 7.80(d, J=8.6Hz, 1H), 7.87(d, J=8.1Hz, 2H). Example 105142 1.75-1.89(m, 2H), 2.31-2.38(m, 2H), 2.54-2.74(m, 11H), 3.04(s, 3H),25 Similar to 3.70(s, 2H), 3.75(s, 6H), 6.30(t, J=2.2Hz, 1H), 6.66(d,J=2.2Hz, 2H), Example 15 7.13-7.20(m, 1H), 7.22-7.32(m, 2H), 7.46(d,J=8.4Hz, 2H), 7.55(d, J=8.4Hz, 2H). Example 106 143 1.65-1.78(m, 2H),2.20-2.29(m, 2H), 2.41-2.61(m, 10H), 2.77(s, 3H), 17 Similar to 2.90(s,3H), 3.57(s, 2H), 3.72-3.79(m, 2H), 4.91-5.04(m, 2H), 5.59-5.75(m,Example 15 1H), 6.39-6.44(m, 1H), 6.55-6.62(m, 1H), 6.80-6.83(m, 1H),6.96-7.08(m, 3H), 7.10-7.18(m, 2H), 7.30″7.39(m, 2H), 7.43(d, J=8.2Hz,2H), 7.76(d, J=8.2Hz, 2H). Example 107 144 1.78-1.82(m, 2H),2.19-2.27(m, 2H), 2.43-2.48(m, 2H), 2.67-2.82(m, 6H), 21 Similar to3.40-3.45(m, 1H), 3.76(s, 2H), 3.99-4.05(m, 2H), 7.14-7.30(m, 10H),Example 1 7.65(d, 2H, J=8.25Hz), 7.96(d, 2H, J=8.25Hz). Example 108 1457.87(d, J=8.2Hz, 2H), 7.54(d, J=8.2Hz, 2H), 7.36-6.94(m, 7H), 10 Similarto 6.68-6.64(m, 1H), 3.79(t, J=6.4Hz, 2H), 3.67(s, 2H), 3.05(s, 3H),2.81(t, Example 15 J=6.4Hz, 2H), 2.71-2.58(m, 10H), 2.44-2.33(m, 2H),1.87-1.82(m, 2H). Example 109 147 1.79-1.90(m, 2H), 2.30-2.41(m, 2H),2.58-2.79(m, 11H), 3.04(s, 3H), 26 Similar to 3.66(s, 2H), 6.65-6.71(m,1H), 6.85-7.00(m, 5H), 7.02-7.20(m, 3H), Example 15 7.25-7.35(m, 2H),7.35-7.45(m, 2H), 7.52(d, J=8.3Hz, 2H), 7.86(d, J=8.3Hz, 2H). Example110 148 1.78-1.90(m, 2H), 2.30-2.40(m, 2H), 2.53-2.79(m, 11H), 3.05(s,3H), 24 Similar to 3.71(s, 2H), 3.83(s, 3H), 5.50(broad s, 1H), 6.84(d,J=8.3Hz, 1H), 6.90(dd, Example 15 J=8.3Hz, 2.0Hz, 1H), 7.04(d, J=2.0Hz,1H), 7.14-7.22(m, 1H), 7.24-7.37(m, 2H), 7.40-7.50(m, 2H), 7.56(d,J=8.2Hz, 2H), 7.88(d, J=8.2Hz, 2H), Example 111 149 1.77-1.90(m, 2H),2.28-2.38(m, 2H), 2.50-2.73(m, 12H), 3.05(s, 3H), 12 Similar to 3.69(s,2H), 3.74(s, 3H), 6.23-6.26(m, 1H), 6.55-6.58(m, 1H), 6.61-6.64(m,Example 15 1H), 7.14-7.20(m, 1H), 7.22-7.33(m, 2H), 7.42-7.49(m, 2H),7.55(d, J=8.3Hz, 2H), 7.88(d, J=8.3Hz, 2H). Example 112 150 7.88(d,J=8.3Hz, 2H), 7.55(d, J=8.3Hz, 2H), 7.47(d, J=7.9Hz, 2H), 67 Similar to7.30-7.09(m, 7H), 7.07(s, 1H), 6.90-6.71(m, 1H), 5.88-5.75(m, 2H),Example 15 5.16-5.08(m, 4H), 3.95-3.80(m, 4H), 3.70(s, 2H), 3.05(s, 3H),2.71-2.56(m, 10H), 2.37-2.33(m, 2H), 1.88-1.77(m, 2H). Example 113 1511.82-1.86(m, 2H), 2.37-2.41(m, 2H), 2.57-2.73(m, 10H), 3.05(s, 3H), 33Simnilar to 3.71(s, 2H), 4.64(s, 2H), 7.15-7.21(m, 4H), 7.26-7.32(m,4H), 7.56(d, 2H, Example 15 J=8.25Hz), 7.88(d, 2H, J=8.25Hz). Example114 152 7.89(d, J=8.6Hz, 2H), 7.56(d, J=8.6Hz, 2H), 7.38-7.16(m, 8H), 2Similar to 7.07(s, 1H), 4.39(d, J=11.8Hz, 1H), 4.01(d, J=11.8Hz, 1H),3.72(s, 2H), Example 15 3.06(d, J=13.3Hz, 1H) 2.90-2.45(m, 11H),2.33-2.14(m, 1H), 1.90-1.77(m, (a) 2H). Example 115 153 7.89(d, J=8.3Hz,4H), 7.76-7.72(m, 2H), 7.57(d, J=8.3Hz, 2H), 24 Similar to 7.36-7.19(m,3H), 3.72(s, 2H), 3.04(s, 3H), 2.82-2.56(m, 11H), 2.39-2.30(m, 1H),Example 14 1.89-1,81(m, 2H). Example 116 154 1.80-1.84(m, 2H), 2.04(m,2H), 2.59-2.69(m, 10H), 3.04(s, 3H), 3.67(s, 58 Similar to 2H), 3.89(s,3H), 6.64-6.67(m, 1H), 7.00-7.19(m, 5H), 7.41-7.44(m, 1H), Example 157.53(d, 2H. J=7.25Hz), 7.61-7.72(m. 2H), 7.85-7.91(m, 3H). Example 117155 0.84-0.89(m, 3H), 1.23-1.37(m, 12H), 1.55-1.58(m, 2H), 1.78-1.79(m,2H), 51 Similar to 2.33(m, 1H), 2.50-2.76(m, 12H), 3.04(s, 3H), 3.65(s,2H), 6.63-6.67(m, Example 15 1H), 6.95(d, 1H, J=7.59Hz), 7.06-7.17(m,4H), 7.33(d, 2H, J=8.25Hz), 7.52(d, 2H. J=8.25Hz), 7.86(d, 2H,J=8.58Hz). Example 118 156 8.48(br s, 1H), 7.72(d, J=8.3Hz, 2H), 7.56(d,J=8.3Hz, 2H), 16 Similar to 7.50-7.47(m, 2H), 7.33-7.17(m, 3H),6.68-6.66(m, 1H), 6.17-6.06(m, 2H), Example 14 3.71(s, 2H), 3.05(s, 3H),3.03(d, J=13.3Hz, 1H), 2.80-2.50(m, 10H), . . . (a) 2.39-2.28(m, 1H),2.13-2.13 9m, 1H), 1.88-1.79(m, 2H). Example 119 157 7.89(d, J=8.3Hz,2H), 7.66-7.62(m, 2H), 7.56(d, J=8.3Hz, 2H), 21 Similar to 7.34-7.18(m,3H), 7.00(s, 2H), 3.71(s, 2H), 3.04(s, 3H), 3.06(d, J=13.3Hz, Example 141H), 2.79-2.51(m, 11H), 2.30-2.17(m, 1H), 1.87-1.78(m, 2H). . . . (a)Example 120 158 1.73-1.83(m, 2H), 2.26-2.44(m, 2H), 2.45-2.75(m, 11H),3.05(s, 3H), 31 Similar to 3.62(s, 2H), 6.60-6.68(m, 1H), 6.88-6.95(m,1H), 7.00-7.02(m, 1H), Example 15 7.07-7.15(m, 1H), 7.31-7.58(m, 5H),7.78-7.88(m, 3H). Example 121 159 7.88(d, J=8.3Hz, 2H), 7.55(d, J=8.3Hz,2H), 7.46(d, J=8.6Hz, 2H), 39 Similar to 7.32-7.05(m, 4H), 6.84-6.82(m,2H), 6.54-6.50(m, 1H), 3.71(s, 2H), Example 17 3.05(s, 3H), 3.03(d,L=13.3Hz, 1H) 2.86-2.53(m, 10H), 2.46-2.33(m, 2H), 1.90-1.77(m, 2H).Example 122 160 7.88(d, J=8.3Hz, 2H), 7.58(d, J=8.3Hz, 2H), 7.46(d,J=7.3 Hz, 2H), 12 Similar to 7.33-7.17(m, 3H), 6.69-6.66(m, 1H),6.17-6.07(m, 2H), 3.97(d, J=5.3Hz, Example 14 2H), 3.74(s, 2H), 3.33(d,J=5.3Hz, 2H), 2.79-2.50(m, 10H), (a), (b) 2.38-2.14(m, 2H), 1.89-1.80(m,2H). Example 123 161 1.76-1.78(m, 2H), 2.31(m, 2H), 2.60-2.67(m, 10H),3.02(s, 3H), 50 Similar to 3.61(s, 2H), 5.75(s, 1H), 6.62-6.65(m, 1H),6.90-6.93(m, 1H), 7.03(s, Example 15 1H), 7.09-7.15(m, 1H), 7.23-7.39(m,9H), 7.49(d, 2H. J=8.25Hz), 7.83(d, 2H, J=8.25Hz). Example 124 163 Thestructure was confirmed by ESI/MS m/e 515.5 (M⁺ + H, C₂₈H₃₂F₂N₂O₃S). 12Similar to Example 9 Example 125 164 1.77-1.90(m, 2H), 2.29-2.38(m, 2H),2.53-2.80(m, 10H), 3.05(s, 3H), 9 Similar to 3.71(s, 2H), 6.35(broad s,1H), 6.90-7.05(m, 4H), 7.35-7.45(m, 4H), 7.55(d, Example 9 J=8.3 Hz,2H), 7.88(d, J=8.3Hz, 2H). Example 126 165 The structure was confirmedby ESI/MS m/e 547.5 (M⁺ + H, C₂₈H₃₂Cl₂N₂O₃S). 10 Similar to Example 9Example 127 166 The structure was confirmed by ESI/MS m/e 547.5 (M⁺ + H,C₂₈H₃₂Cl₂N₂O₃S). 6 Similar to Example 9 Example 128 167 1.78-1.89(m,2H), 2.30-2.38(m, 2H), 2.54-2.76(m, 11H), 3.05(s, 3H), 12 Similar to3.70(s, 2H), 3.77(s, 6H), 6.69-6.75(m, 2H), 6.97-7.03(m, 2H),7.07-7.10(m, Example 9 2H), 7.16-7.24(m, 2H), 7.55(d, J=8.3Hz, 2H),7.88(d, J=8.3Hz, 2H). Example 129 168 Tbe structure wes confirmed byESI/MS m/e 539.5 (M⁺ + H, C₃₀H₃₀N₂O₅S). 67 Similar to Example 12 Example130 169 1.76-1.92(m, 2H), 2.28-2.40(m, 2H), 2.52-2.77(m, 10H), 52Similar to 3.06(s, 3H), 3.70(s, 2H), 6.68(dd, J=7.9 and 1.7Hz, 1H),Example 15 6.82-6.93(m, 1H), 6.95-7.03(m, 2H), 7.13-7.31(m, 4H), 7.55(d,J=8.6Hz, 2H), 7.88(d, J=8.6Hz, 2H). Example 131 170 1.77-1.90(m, 2H),2.25-2.39(m, 2H), 2.52-2.78(m, 10H), 62 Similar to 3.06(s, 3H), 3.70(s,2H), 6.68(dd, J=7.9 and 2.3Hz. 1H), 6.92-7.02(m, Example 15 2H),7.12-7.35(m, 4H), 7.49(s, 1H), 7.55(d, J=8.3Hz, 2H), 7.88(d, J=8.3Hz,2H). Example 132 171 1.75-1.89(m, 2H), 2.28-2.40(m, 2H), 2.51-2.75(m,10H), 60 Similar to 3.05(s, 3H), 3.69(s, 2H), 6.67(dd, J=7.9 and 2.3Hz,1H), Example 15 6.94(d, J=8.25Hz, 1H), 6.99(d, J=2.3Hz, 1H), 7.16(dd,J=7.9 and 7.9Hz, 1H), 7.25(d, J=8.3Hz, 2H), 7.39(d, J=8.3Hz, 2H),7.54(d, J=8.3Hz, 2H), 7.88(d, J=8.3Hz, 2H). Example 133 172 1.70-1.81(m,2H), 2.25-2.34(m, 2H), 2.50-2.72(m, 12H), 3.03(s, 22 Similar to 3H),3.60(s, 2H), 3.69(s, 6H) 6.23-6.27(m, 1H), 6.59-6.68(m, 3H), Example 156.88-6.95(m, 1H), 7.07-7.17(m, 2H), 7.48(d, J=8.3Hz, 2H), 7.83(d,J=8.3Hz, 2H). Example 134 173 1.70-1.81(m, 2H), 2.26-2.37(m, 2H)2.50-2.70(m, 12H), 3.03(s, 33 Similar to 3H), 3.60(s, 2H), 3.72(s, 3H),6.60-6.72(m, 2H), 6.90-6.95(m, 1H), Example 15 6.95-7.00(m, 1H),7.01-7.19(m, 4H), 7.48(d, J=8.3Hz, 2H), 7.83(d, J=8.3Hz, 2H). Example135 197 7.88(d, J=8.3Hz, 2H), 7.56(d, J=8.3Hz, 2H), 7.51-7.47(m, 4H), 41Similar to 7.30-7.13(m, 6H), 3.71(s, 2H), 3.05(s, 3H), 2.73-2.46(m, 8H),1.85-1.76(m, Example 9 4H), 1.62-1.59(m, 2H). Example 136 198 7.83(d,J=8.3Hz, 2H), 7.43(d, J=8.4Hz, 2H), 7.17-7.07(m, 4H), 6.91(d, 11 Similarto J=7.6Hz, 2H), 3.56(s, 2H), 3.04(s, 3H), 2.62-2.42(m, 12H), 1.8(br s),Example 12 1.75-1.50(m, 4H). Example 137 200 1.74-1.84(m, 2H),2.11-2.21(m, 2H), 2.36-2.43(m, 2H), 2.59-2.67(m, 4H), 70 Similar to3.31-3.37(m, 4H), 3.97(t, J=7.6Hz, 1H), 7.12-7.30(m, 10H), 7.48(d,Example 3 J=8.6Hz, 2H), 7.72(d, J=8.6Hz, 2H). Example 138 2011.69-1.79(m, 1H), 1.89-1.99(m, 1H), 2.13-2.28(m, 2H), 2.37-2.49(m, 2H),57 Similar to 2.54-2.62(m, 2H), 2.64-2.69(m, 1H), 2.75-2.80(m, 1H),3.33-3.39(m, 2H), Example 3 3.73-3.78(m, 2H), 4.01(dd, J=17.5, 7.6Hz,1H), 7.13-7.32(m, 12H), 8.63-8.69(m, 2H). Example 139 203 1.70-1.85(m,2H), 2.14-2.25(m, 2H), 2.30(d, J=2.0Hz, 3H), 2.34-2.45(m, 38 Similar to2H), 2.49-2.57(m, 2H), 2.60-2.68(m, 2H), 3.15(d, J=7.9Hz, 2H), Example 43.48-3.60(m, 6H), 3.99(dt, J=2.0, 7.6Hz, 1H), 7.12-7.32(m, 15H). Example140 205 0.87(t, J=7.3Hz; 3H), 1.40-1.55(m, 2H), 1.71-1.81(m, 2H),2.16-2.25(m, 25 Similar to 2H), 2.37-2.45(m, 4H), 2.52-2.71(m, 8H),4.00(t, J=7.9Hz, 1H), Example 5 7.12-7.20(m, 2H), 7.20-7.31(m, 8H).Example 141 208 1.74-1.83(m, 2H), 2.17-2.26(m, 2H), 2.40-2.47(m, 2H),2.63-2.75(m, 8H), 30 Similar to 3.44(s, 2H), 4.00(t, J=7.6Hz, 1H),5.51(s, 1H), 7.13-7.32(m, 10H). Example 6 Example 142 209 1.72-1.81(m,2H), 2.17-2.27(m, 2H), 2.39-2.49(m, 2H), 2.47(t, J=7.6Hz, 64 Similar to2H), 2.63-2.73(m, 8H), 2.84(t, J=7.6Hz, 2H), 3.67(s, 3H), 3.99(t,Example 1 J=7.6Hz, 1H), 7.12-7.20(m, 2H), 7.22-7.31(m, 8H). Example 143235 2.17-2.35(m, 4H), 2.35-2.60(m, 8H), 3.50(s, 2H), 3.97(t, J=7.3Hz,1H), 17 Similar to 7.11-7.35(m, 12H), 8.53(d, J=5.9Hz, 2H). Example 8Example 144 238 1.77-1.86(m, 2H), 2.18-2.27(m, 2H), 2.40-2.46(m, 2H),2.66-2.72(m, 4H), 11 Similar to 2.78-2.88(m, 6H), 2.91-2.98(m, 2H),4.01(t, J=7.6Hz, 1H), 6.97(s, 1H), Example 5 7.01-7.31(m, 12H), 7.35(d,J=7.9Hz, 1H), 7.61(d, J=7.9Hz, 1H), 7.94(br, 1H). Example 145 2391.68-1.78(m, 2H), 2.14-2.24(m, 2H), 2.24(s, 3H), 2.32(s, 3H),2.36-2.43(m, 28 Similar to 2H), 2.53-2.67(m, 8H), 3.30(s, 2H), 4.00(t,J=7.6Hz, 1H), 7.12-7.19(m, 2H), Example 7 7.21-7.56(m, 8H). Example 146240 1.75-1.82(m, 2H), 2.19-2.26(m, 2H), 2.43-2.47(m, 2H), 2.65-2.73(m,8H), 50 Similar to 3.63(s, 2H), 4.01(t, J=7.8Hz, 1H), 7.14-7.19(m, 2H),7.23-7.29(m, 10H), Example 1 8.52(d, J=5.9Hz, 2H). Example 147 2411.74-1.83(m, 2H), 2.18-2.27(m, 2H), 2.42-2.48(m, 2H), 2.66-2.74(m, 8H),44 Similar to 3.63(s, 2H), 4.00(t, J=7.6Hz, 1H), 7.12-7.30(m, 11H),7.66(ddd, J=7.9, Example 1 2.0, 1.7Hz, 1H), 8.49(dd, J=4.6, 1.7Hz, 1H),8.53(d, J=2.0Hz, 1H), Example 148 242 1.78-2.00(m, 2H), 2.20-2.31(m,2H), 2.44-2.52(m, 2H), 2.68-2.82(m, 8H), 57 Similar to 3.80(s, 2H),4.01(t, J=7.6Hz, 1H), 7.12-7.30(m, 11H), 7.43(d, J=7.9Hz Example 1 1H),7.64(ddd, J=7.9, 7.6, 1.7Hz, 1H), 8.53(ddd, J=5.0, 1.7, 1.0Hz, 1H).Example 149 243 1.7-1.83(m, 2H), 2.1-2.25(m, 2H), 2.43(t, J=7.4Hz, 2H),2.4-2.74(m, 32 Similar to 8H), 3.69(s, 2H), 3.75(s, 3H), 3.96(t,J=7.7Hz, 1H), 6.81(d, J=8.9Hz, Example 1 2H), 7.16(d, J=8.6Hz, 2H),7.2-7.35(m, 7H), 8.51(d, J=5.9Hz, 2H). Example 150 245 1.70-1.85(m, 2H),2.12-2.22(m, 2H), 2.37-2.45(m, 2H), 2.63-2.72(m, 8H), 8 Simnilar to3.63(s, 2H), 4.00(t, J=7.6Hz, 1H), 7.15-7.29(m, 11H), 7.87(d, J=4.6Hz,Example 1 2H). Example 151 258 1.80-1.88(dt, J=12.2, 5.9Hz, 2H),2.40(dd, J=6.0, 5.2Hz, 2H), 8 Similar to 2.57-2.74(m, 10H), 3.63(s, 2H),7.15-7.20(m, 2H), 7.26-7.32(m, 6H), Example 1 7.45-7.48(m, 4H), 8.52(dd,J=4.3, 1.6Hz, 2H). (a) 2-(Trimethylsilyl)ethoxymethyl group was used asprotective group. (b) Compound No. 160 was obtained as the by-product inpreparation of compound No. 156.

General Alkylation Procedure of1-(3-Hydroxy-3,3-diphenylpropyl)homopiperazine for Examples 152-162

A solution of 1-(3-hydroxy-3,3-diphenylpropyl)homopiperazine (0.12 mmol)in 0.5 mL of acetonitrile was treated with alkylating reagent (0.10mmol) and potassium carbonate (0.15 mmol) and the reaction mixture washeated to 50° C. for 5 h. Polystyrene-linked benzyl isocyanate resin(0.65 mmol/g, 0.05 mmol) and dichloromethane (0.5 mL) was added and themixture was stirred at room temperature for 1 h. The mixture wasfiltered and washed with dichloromethane (0.5 mL). The filtrate andwashing were combined, and the solvent was removed under reducedpressure to afford the N,N-dialkylated material.

Example 152

Compound No. 174 (65 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 493.0 (M⁺+H, C₂₉H₃₆N₂O₃S).

Example 153

Compound No. 175 (51 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 507.5 (M⁺+H, C₃₀H₃₈N₂O₃S).

Example 154

Compound No. 176 (48 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 507.5 (M⁺+H, C₃₀H₃₈N₂O₃S).

Example 155

Compound No. 177 (51 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 521.5 (M⁺+H, C₃₁H₄₀N₂O₃S).

Example 156

Compound No. 178 (56 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 541.5 (M⁺+H, C₃₂H₃₆N₂O₃S).

Example 157

Compound No. 179 (41 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 479.0 (M⁺+1, C₂₈H₃₄N₂O₃S).

Example 158

Compound No. 180 (42 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 493.0 (M⁺+1, C₃₉H₃₆N₂O₃S).

Example 159

Compound No. 181 (42 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 507.5 (M⁺+1, C₃₀H₃₈N₂O₃S).

Example 160

Compound No. 182 (53 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 507.5 (M⁺+1, C₃₀H₃₈N₂O₃S).

Example 161

Compound No. 183 (40 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 521.5 (M⁺+1, C₃₁H₄₀N₂O₃S).

Example 162

Compound No. 184 (52 mg) was prepared by above general alkylationprocedure. ESI/MS m/e 541.5 (M⁺+1, C₃₃H₃₆N₂O₃S).

Preparation of 1-(3,3-Diphenylpropyl)homopiperazine

A suspension of homopiperazine (2.9 g, 28.9 mmol) and homopiperazinedihydrochloride (5.0 g. 28.9 mmol) in EtOH was heated to 70° C. for 2 h,at which point a homogeneous solution of monohydrochloride salt (2.5equiv) was obtained. The reaction mixture was treated with3,3-diphenylpropyl methanesulfonate (6.7 g, 23.1 mmol, 1 equiv) and NaI(8.65 g, 57.7 mmol, 2.5 equiv) and heated to reflux for 16 h. Thereaction mixture was cooled to 25° C. and the solvent was removed invacuo. The crude product was partitioned between 2N aqueous NaOH (100mL) and EtOAc (100 mL), and the aqueous layer was extracted with EtOAc(3×50 mL). The combined organic phase was washed with saturated aqueousNaCl (1×100 mL), dried (MgSO₄) and concentrated. Chromatography (SiO₂,4×20 cm. 10% CH₃OH— 5% Et₃N-CH₂Cl₂) afforded the monoalkylated product(6.44 g, 6.79 g theoretical, 95%) as an amber oil.

General Alkylation of 1-(3,3-Diphenylpropyl)homopiperazine for Examples163-194

A solution of 1-(3,3-diphenylpropyl)homopiperazine (132 mg, 0.449 mmol)was treated with alkylating reagent (0.492 mmol, 1.1 equiv) and Et₃N (75mL, 0.54 mmol, 1.2 equiv) and the reaction mixture was heated to 70° C.for 16 h. The solvent was removed under vacuum. Chromatography (SiO₂,2×20 cm, 20% CH₃OH-EtOAc) afforded the N,N-dialkylated material(10-95%).

Chromatography Methods

HPLC analyses was performed with following methods.

1. Methods A and S.

Column

Method A: Micra Analytical Column (4.6 mm×3.3 cm)

Method B: Monitor C18 column (50 mm×4.6 mm)

Buffer for Methods A and B

Buffer A: 0.05% TFA in H₂O

Buffer B: 0.035% TFA in 10% H₂O/CH₃CN

Gradient 1 (10-11 Min)

1% Buffer B for 0.5 min

1 to 31% Buffer B in 5.0 min

31% to 51% Buffer B in 2.0 min

51% Buffer B for 0.5 min

51% to 1% Buffer B in 0.5 min

1% Buffer B Hold

Gradient 2 (4 Min)

10% Buffer B for 0.5 min

61% Buffer B in 1.8 min

91% Buffer B in 1.5 min

91% Buffer B for 0.8 min

91% to 10% Buffer B in 0.4 min

10% Buffer B Hold

2. Method C

Column

C18 column 4.6 mm

Gradient

1% Buffer B for 3 min

1% to 61% Buffer B in 20 min

61% Buffer B For 4 min

61% to 1% Buffer B in 1 min

1% Buffer B for 5 min—hold

Example 163

Compound No. 265 (82 mg, 39%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (151.7 mg, 0.513 mmol) andN,N-diethylacetamide (78 mL, 0.567 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=4.93 min (90%), 220 nm (Method A);ESI/MS m/e 408.4 (M⁺+H, C₂₆H₃₇N₃O).

Example 164

Compound No. 210 (53 mg. 34%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (131 mg, 0.446 mmol) and1-bromo-2-butyne (42 mL, 0.479 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=16.18 min (>90%), 220 nm (Method C);ESI/MS m/e 347.2 (M⁺+H, C₂₄N₃₀N₂).

Example 165

Compound No. 211 (102 mg, 75%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (115 mg, 0.391 mmol) and(bromomethyl)cyclopropane (42 mL, 0.433 mmol, 1.1 equiv) employinggeneral alkylation procedure. RPLC t_(R)=17.91 min (>95%), 220 nm(Method C): ESI/MS m/e 349.4 (M⁺+H, C₂₄H₃₂N₂).

Example 166

Compound No. 266 (150 mg, 95%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (132 mg, 0.449 mmol) and2-bromoacetamide (68 mg, 0.492 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=6.10 min (90%), 220 nm (Method A).ESI/MS m/e 352.2 (M⁺+H. C₂₂H₂₉N₃O).

Example 167

Compound No. 212 (21 mg. 9%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (151 mg, 0.513 mmol) and7-acetoxy-4-(bromomethyl)coumarin (168 mg, 0.565 mmol, 1.1 equiv)employing general alkylation procedure. RPLC t_(R)=5.73 min (>90%), 220nm (Method A); ESI/MS m/e 469.4 (M⁺+H. C₃₀H₃₂N₂O₃).

Example 168

Compound No. 213 (164 mg, 94%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (136.6 mg, 0.465 mmol) and5-bromovaleronitrile (60 mL, 0.511 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=17.75 min (>90%), 220 nm (Method C);ESI/MS m/e 376.4 (M⁺+H, C₂₆H₃₃N₃).

Example 169

Compound No. 70 (132 mg, 89%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and2-chloro-N-(2,6-diethylphenyl)acetamide (70 mg, 0.310 mmol, 0.9 equiv)employing general alkylation procedure. RPLC t_(R)=6.97 min (88%), 220nm (Method A): ESI/MS m/e 484.4 (M⁺+H, C₃₂H₄₁N₃O).

Example 170

Compound No. 214 (49 mg, 42%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and3-bromopropionitrile (31 mL, 0.374 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=4.36 min (>90%), 220 nm (Method A);ESI/MS m/e 348.2 (M⁺+H, C₂₃H₂₉N₃).

Example 171

Compound No. 215 (71 mg, 58%) was prepared from1-3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and4-bromobutyronitrile (37 mL, 0.374 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=3.91 min (86%), 220 nm (Method A);ESI/MS m/e 362.2 (M⁺+H, C₂₄H₃₁N₃).

Example 172

Compound No. 267 (31 mg, 24%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) andN-ethylchloroacetamide (45 mg, 0.374 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=4.07 min (91%), 220 nm (Method A);ESI/MS m/e 380.4 (M⁺+H, C₂₄H₃₃N₃O).

Example 173

Compound No. 204 (29 mg, 17%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (105.4 mg, 0.359 mmol) and methyl2-[3-(2-chloroethyl)ureido]benzoate (110 mg, 0.394 mmol, 1.1 equiv)employing general alkylation procedure. RPLC t_(R)=4.95 min (>95%), 220nm (Method A); ESI/MS m/e 483.4 (M⁺+H, C₃₀H₃₅N₄O₂).

Example 174

Compound No. 216 (79 mg, 36%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (136.7 mg, 0.465 mmol) andMaybridge SPE03660 (108.8 mg, 0.511 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=5.83 min (>90%), 220 nm (Method A);ESI/MS m/e 471.4 (M⁺+H, C₂₉H₃₄N₄O₂).

Example 175

Compound No. 246 (59 mg, 33%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeGK02253 (87 mg, 0.374 mmol) employing general alkylation procedure. RPLCt_(R)=5.11 min (>95%), 220 nm (Method A); ESI/MS m/e 491.4 (M⁺+H,C₂₈H₃₄N₄O₂S).

Example 176

Compound No. 217 (66 mg, 58%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) andbromoacetonitrile (26 mL, 0.374 mmol) employing general alkylationprocedure. RPLC t_(R)=5.21 min (>95%), 220 nm; ESI/MS m/e 334.4 (M⁺+H,C₂₂H₂₇N₃).

Exmple 177

Compound No. 71 (59 mg, 33%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeCD08063 (100 mg, 0.374 mmol, 1.1 equiv) employing general alkylationprocedure. RPLC t_(R)=6.23 min (>85%), 220 nm (Method A); ESI/MS m/e525.2 (M⁺+H, C₂₈H₃₃ClN₄O₂S).

Example 178

Compound No. 247 (35 mg, 221) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeSEW03081 (63 mg, 0.374 mmol) employing general alkylation procedure.RPLC t_(R)=6.20 min (90%), 220 nm (Method A); ESI/MS m/e 427.4 (M⁺+H,C₂₂H₂₇ClN₄S).

Example 179

Compound No. 74 (42 mg, 23%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeS52956 (85 mg, 0.374 mmol) employing general alkylation procedure. RPLCt_(R)=21 min (901), 220 nm (Method A); ESI/MS m/e 486.4 (M⁺+H,C₃₁H₃₉N₃O₂).

Example 180

Compound No. 248 (105 mg, 41%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (133.5 mg, 0.454 mmol) andMaybridge GK1350 (149 mg, 0.500 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=6.60 min (>90%), 220 nm (Method A);ESI/MS m/e 556.4 (M⁺+H, C₃₂H₃₇N₅O₂S).

Example 181

Compound No. 249 (80 mg, 34%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (126.7 mg, 0.430 mmol) andMaybridge RF00404 (134 mg, 0.474 mmol, 1.1 equiv) employing generalalkylation procedure. RPLC t_(R)=5.96 min (>90%), 220 nm (Method A):ESI/MS m/e 540.4 (M⁺+H, C₂₈H₃₁Cl₂N₅O₂).

Example 182

Compound No. 219 (69 mg, 38%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeS07335 (117 mg, 0.408 mmol, 1.2 equiv) employing general alkylationprocedure. RPLC t_(R)=4.68 min (>95%), 220 nm (Method A); ESI/MS m/e526.4 hydrolysis product (M⁺+H, C₃₆H₃₇N₃O₂).

Example 183

Compound No. 269 (20 mg, 13%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeCD07922 (67 mg, 0.374 mmol, 1.1 equiv) employing general alkylationprocedure. RPLC t_(R)=4.65 min (90%), 220 nm (Method A): ESI/MS m/e438.3 (M⁺+H, C₂₆H₃₆N₃OS).

Example 184

Compound No. 250 (24 mg, 19%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeSEW00285 (89 mg) employing general alkylation procedure. RPLC t_(R)=4.70min (>90%), 220 nm (Method A); ESI/MS m/e 377.3 (M⁺+H, C₂₃H₂₈N₄O).

Example 185

Compound No. 220 (67 mg, 63%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and propargylbromide (38 mg, 0.32 mmol) and potassium iodide (0.037 g, 0.22 mmol)employing general alkylation procedure. TLC R_(f)=0.29 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=4.21 min (>85%), 220 nm (Method A); ESI/MS m/e333,3 (M⁺+H, C₂₃H₃₆N₂).

Example 186

Compound No. 221 (51 mg, 32%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (85 mg, 0.408 mmol)employing general alkylation procedure. RPLC t_(R)=4.70 min (>97%), 220nm (Method B); ESI/MS m/e 469.3 (M⁺+H, C₃₀H₃₆N₄O).

Example 187

Compound No. 222 was synthesized from1-(3,3-diphenylpropyl)homopiperazine (200 mg, 0.680 mmol) and2-(tert-butyldiphenylsilyl)-3-bromo-2-methyl-1-propanol (125 mg, 0.32mmol) employing general alkylation procedure. R_(f) 0.53 (10%CH₃OH—CH₂Cl₂). The purified intermediate was dissolved in anhydrous THFand treated with tert-butylammonium fluoride (0.35 mL, 0.35 mmol, 1.1equiv). The reaction mixture was stirred at 25° C. for 2 h andconcentrated. Chromatography (SiO₂, 40 g, 20% CH₃OH-EtOAc) afforded thedesired product (30 mg, 30%, two steps). TLC R_(f) 0.17 (conditions);RPLC t_(R)=4.16 min (>85%), 220 nm (Method B); ESI/MS m/e 367.3 (M⁺+H,C₂₄H₃₄N₂O).

Example 188

Compound No. 75 (91 mg, 65%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) andα-bromo-o-tolunitrile (80 mg, 0.406 mmol) employing general alkylationprocedure. RPLC t_(R)=6.52 min (>98%), 220 nm (Method B); ESI/MS m/e410.3 (M⁺+H, C₂₈H₃₁N₃).

Example 189

Compound No. 76 (63 mg, 37%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and2-bromoacetamido-4-nitrophenol (111 mg, 0.406 mmol) employing generalalkylatlon procedure. RPLC t_(R)=6.55 min (>98%), 220 nm (Method B);ESI/MS m/e 489.3 (M⁺+H, C₂₈H₃₂N₄O₄).

Example 190

Compound No. 77. (103 mg, 61%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and ethyl4-(2-chloroacetamido) benzoate (98 mg, 0.406 mmol) employing generalalkylation procedure. RPLC t_(R)=6.52 min (>98%), 220 nm (Method B);ESI/MS m/e 500.3 (M⁺+H, C₃₁H₃₇N₄O₃).

Example 191

Compound No. 223 (84 mg, 49%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and1-(3-chloropropyl)theobromine (104 mg, 0.406 mmol) employing generalalkylation procedure. RPLC t_(R)=5.25 min (>98%), 220 nm (Method B);ESI/MS m/e 515.3 (M⁺+H, C₃₀H₃₈N₆O₂).

Example 192

Compound No. 80 (81 mg, 47%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and4-nitrobenzyl bromoacetate (111 mg, 0.406 mmol) employing generalalkylation procedure. RPLC t_(R)=7.35 min (>98%), 220 nm (Method B);ESI/MS m/e 488.3 (M⁺+H, C₂₉H₃₃N₃O₄).

Example 193

Compound No. 81 (139 mg, 921) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and2-hydroxy-5-nitrobenzyl bromide (90 mg, 0.406 mmol) employing generalalkylation procedure. RPLC t_(R)=5.90 min (>95%), 220 nm (Method B);ESI/MS m/e 446.3 (M⁺+H, C₂₇H₃₁N₃O₃).

Example 194

Compound No. 268 (34 mg, 25%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) andN-(chloroacetyl)isopropylamine (51 mg, 0.374 mmol) employing generalalkylation procedure. RPLC t_(R)=5.47 min (>90%), 220 nm (Method B);ESI/MS m/e 394.4 (M⁺+H, C₂₅H₃₅N₃O).

General Epozide Opening with 1-(3,3-Diphenylpropyl)homopiperazine forExamples 195-197

A solution of 1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol)in CH₃CN (1.8 mL) was treated with epoxide (0.374 mmol, 1.1 equiv) and¹Pr₂NEt (71 mL, 0.41 mmol, 1.2 equiv), and the reaction mixture washeated to 70° C. for 16 h. The solvent was removed under reducedpressure. Chromatography (SiO₂, 2×20 cm, 20% CH₃OH-EtOAc) afforded theN,N-dialkylated material (23-83%).

Example 195

Compound No. 218 (114 mg, 83%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and MaybridgeNRB00767 (42 mg, 0.375 mmol) employing general epoxide openingprocedure. RPLC t_(R)=3.77 min (>85%), 220 nm (Method A); ESI/MS m/e407.4 (M⁺+H, C₂₇H₃₆N₂O₂).

Example 196

Compound No. 253 (35 mg, 23%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and furfurylglycidyl ether (63 mg, 0.406 mmol) employing general epoxide openingprocedure. RPLC t_(R)=5.70 min (>98%), 220 nm (Method B); ESI/MS m/e449.3 (M⁺+H, C₂₈H₃₆N₄O₃).

Example 197

Compound No. 225 (69 mg, 70%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (40.3 mg, 0.137 mmol) andN-(2,3-epoxypropyl)phthalimide (42.6 mg, 0.150 mmol) employing generalepoxide opening procedure. TLC R_(f)=0.40 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.96 min (>85%), 220 nm (Method B-10 min); ESI/HS m/e 498.3 (M⁺+H,C₃₁H₃₅N₃O₃).

Preparation of N,N-Diethyl-(1-Homopiperazinyl)acetamide

Acetyl chloride (3.90 mL, 54.9 mmol) was dissolved in EtOH (166 mL) andthe mixture was stirred for 30 min at 25° C. A solution ofhomopiperazine (5.0 g. 50 mmol, 1 equiv) in EtOH (20 mL) was added tothe reaction mixture in one portion. The flask was fitted with a refluxcondenser with a CaCl₂ drying tube and the reaction mixture was heatedto reflux for 1 h. N,N-Diethylchloroacetamide (3,37 g, 0.5 equiv) wasadded and the reaction was heated to reflux for an additional 16 h. Thereaction mixture was allowed to cool and the solvent was removed invacuo. The product was partitioned between EtOAc (150 mL) and saturatedaqueous NaHCO₃ (100 mL). The aqueous phase was extracted with EtOAc(1×100 mL). The combined organic phase was dried (Na₂SO₄), filtered andconcentrated to yield the symmetrically dialkylated material (0.950 g,17%). The aqueous phase was basicified with 1 M NaOH (100 mL) and wasextracted CH₂Cl₂ (1×150 mL, 2×100 mL). The combined organic phase wasdried (Na₂SO₄), filtered and concentrated to afford the puremonoalkylated homopiperazine (2.4 g, 45%).

Preparation of 1-(4-Cyanobenzyl)homopiperazine

To a solution of homopiperazine (9.2 g, 92 mmol, 2 equiv). in EtOH (115mL) was added 1 M HCl-EtOH (92 mL) dropwise over 1 h. The suspension washeated to 70° C. for 1 h at which point a homogeneous solution ofmonohydrochloride salt was obtained. α-Bromo-p-tolunitrile (9.0 g, 46mnmol, 1 equiv) was added and the reaction mixture was heated to refluxfor 5 h. After cooling, the solvent was removed by rotary evaporationand the residue was partitioned between CH₂Cl₂ (100 mL) and 2N aqueousKOH (100 mL). The aqueous layer was extracted with CH₂Cl₂ (5×50 mL) andthe combined organic phase was washed with saturated aqueous NaCl (1×150mL) and dried (MgSO₄). Chromatography (SiO₂, 4×20 cm, 20% CH₃OH —5%Et₃N—CH₂Cl₂) afforded the desired monoalkylated material (6.78 g, 10.1 gtheoretical, 67%) as an amber oil.

Preparation of 1-[4-(Methylsulfonyl )benzyl]homopiperazine

To a 2-neck, 2-L round bottom flask containing anhydrous EtOH (800 mL)and equipped with a mechanical stirrer and condenser was added acetylchloride (20.2 mL, 0.267 mol, 1.1 equiv). The solution was stirred for0.5 h and homopiperazine (24.3 g, 0.243 mol) was added, The mixture washeated to reflux for 2 h. The reaction mixture was cooled to 25° C.,4-(methylsulfonyl)benzyl chloride (25 g, 0.122 mol, 0.5 equiv) was addedand the reaction mixture heated to reflux for 16 h. The reaction mixturewas cooled to 25° C. and the solvent was removed under vacuum. Theresidue was diluted with EtOAc (500 mL) and was washed with 2N KOH(2×500 mL). The aqueous layer was extracted with EtOAc (1×500 mL). Theorganic phase was combined, washed with 2N KOH (1×300 mL), dried (MgSO₄)and concentrated. The crude solid was washed with hot EtOAc to yieldpure desired product (8.03 g, 32.7 g theoretical, 25%) as an off-whitesolid, TLC R₁ 0.04 (10% CH₃OH—CH₂Cl₂); ¹H NMR (CDCl₃, 300 MHz) δ 9.82(br s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.60 (d, J=7.7 Hz, 2H), 3.80 (br s,2H), 3.36 (br m, 2H), 3.07 (s, 3H), 2.93 (br s, 2H), 2.80 (br s, 2H),2.12 (br m, 2H).

Preparation of 1-(4-Picolyl)homopiperazine

A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved inanhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution ofhomopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reactionmixture was heated to reflux for 1 h, cooled to 25° C. and a solution of4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) wasadded. The reaction mixture was heated to reflux for 16 h, cooled to 25°C. and the solvent was removed under vacuum. The residue was dilutedwith CH₂Cl₂ (300 mL) and was washed with 2N KOH (1×300 mL). The aqueouslayer was extracted with CH₂Cl₂ (1×300 mL) and the organic phase waswashed with 2N KOH (150 mL), dried (MgSO₄) and concentrated.Chromatography (SiO₂, 5% H₂O-5% NH₄OH—¹PrOH) afforded the desiredproduct (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC R_(f)0.45 (5% H₂O-5% NH₄OH—¹PrOH): ¹H NMR (CDCl₃, 300 MHz) δ 8.77 (d, J=5.9Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m,4H), 2.04 (m, 2H).

Preparation of 1-(4-Chlorobenzyl)homopiperazine

Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine(15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and thereaction mixture was heated to reflux for 16 h before concentrating. Theresidue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH(50 mL). The aqueous layer was extracted with EtOAc (200 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentrated invacuo. Chromatography (double separation. SiO₂, 20×7 cm,¹PrOH—H₂O—NH₄OH, 80:12:6 to 70:20:10 gradient elution) afforded thedesired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36g, 16.5%). GC/MS m/e 224 (M⁺, C₁₂H₁₇N₂Cl).10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH⁺+H,C₃₁H₃₅N₃O₃).

Preparation of1-(4-Methyl-2-thtienyl)-2-(1-homopiperazinylacetyl)hydrazine

1-(tert-butyloxycarbonyl)homopiperazine (1.0 g, 5.0 mmol) in CH₃CN (25mL) was treated with Maybridge GK 02253 (1.2 g, 5.0 mmol) and ¹Pr₂NEt(1.04 mL, 6.0 mmol, 1.2 equiv). The reaction mixture was heated to 70°C. for 16 h. After cooling, the solvent was removed under reducedpressure and the residue was purified by chromatography (SiO₂, 4×20 cm,5% CH₃OH—CH₂Cl₂) to afford the Boc-protected monoalkylated material as awhite foam (1.33 g, 67%). RPLC t_(R)=5.20 min (>98%), 220 nm (Method B);ESI/MS m/e 397.0 (M⁺+H, C₁₈H₃₈N₄O₄S). The product (1.1 g, 2.8 mmol) wasdissolved in 3 M HCl—CH₃OH (14 mL) and stirred at 25° C. for 30 min. Thesolvent was removed by rotary evaporation and the deprotectedhomopiperazine HCl salt was dissolved in ^(t)BuOH-H₂O (3:1, 25 mL).Dowex Anion exchange resin was added until pH=9. The resin was removedby filtration and evaporation afforded the pure mono-alkylated product(703 mg, 86%). RPLC t_(R)=0.78 min (>98%), 220 nm (Method B); ESI/MS m/e297.1 (M⁺+H, C₁₄H₃₀N₄O₂S).

General Alkylation with 4-Bromo-2,2-diphenylbutyronitrile for Examples198-203

Monosubstituted homopiperazine (100 mg, 0.468 mmol, 1.0 equiv) in CH₃CN(3 mL) was treated sequentially with 4-bromo-2,2-diphenylbutyronitrile(168 mg, 0.561 mmol, 1.2 equiv) followed by ¹Pr₂NEt (60 mg, 0.468 mmol,1.2 equiv). The reaction mixture was heated to 70° C. with stirring for16 h. The mixture was allowed to cool and the solvent was removed invacuo. The product was purified by chromatography (SiO₂, 3×5 cm, 20%CH₃OH-EtOAC) to afford the desired dialkylated material (48 mg, 24%).

Example 198

Compound No. 264 (48 mg, 24%) was prepared fromN,N-diethyl-(1-homopiperazinyl)acetamide (100 mg, 0.468 mmol) and4-bromo-2,2-diphenylbutyronltrile (168 mg, 0.561 mmol) employing generalalkylation procedure. TLC R_(f)=0.30 (20% CH₃OH-EtOAc); RPLC t_(R)=4.58min (>98%), 220 nm (Method B); ESI/MS m/e 433,3 (M⁺+H, C₂₇H₃₆N₄O).

Example 199

Compound No. 233 (225 mg, 73%) was prepared from1-(4-picolyl)homopiperazine (200 mg, 1.05 mmol) and4-bromo-2,2-diphenylbutyronitrile (225 mg, 0.75 mmol) employing generalalkylation procedure. TLC R_(f)=0.33 (10% CH₃OH—CH₂Cl₂), RPLC t_(R)=4.27min (>85%), 220 nm (Method B); ESI/MS m/e 411.3 (MH⁺+H, C₂₇H₃₀N₄).

Example 200

Compound No. 2 (155 mg, 52%) was prepared from1-(4-cyanobenzyl)homopiperazine (150 mg, 0.684 mmol) and4-bromo-2,2-diphenylbutyronitrile (226 mg, 0.752 mmol, 1.1 equiv)employing general alkylation procedure. RPLC t_(R)=4.93 min (85.1%), 220nm (Method B); ESI/MS m/e 435.3 (M⁺+H, C₂₉H₃₀N₄).

Example 201

Compound No. 3 (16 mg, 12%) was prepared from1-(4-chlorobenzyl)homopiperazine (68 mg, 0.30 mmol) and4-bromo-2,2-diphenylbutyronitrile (100 mg, 0.33 mmol) employing generalalkylation procedure. TLC R_(f)=0.32 (5% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.27min (>85%), 220 nm (Method A); ESI/MS m/e 444.3 (M⁺+H, C₂₀H₃₀ClN₂).

Example 202

Compound No. 4 (251 mg, 69%) was prepared from1-[4-(methylsulfonyl)benzyl]homopiperazine (200 mg, 0.75 mmol) and4-bromo-2,2-diphenylbutyronitrile (270 mg, 0.9 mmol) employing generalalkylation procedure. TLC R_(f)=0.53 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=4.73min (>85%), 220 nm (Method A); ESI/MS m/e 488.3 (M⁺+H, C₂₉H₃₃N₂O₂S).

Example 203

Compound No. 234 (9 mg, 5%) was prepared from1-(4-methyl-2-thienyl)-2-(1-homopiperazinylacetyl)hydrazine (95 mg, 0.32mmol) and 4-bromo-2,2-diphenylbutyronitrile (96 mg, 0.32 mmol) employinggeneral alkylation procedure. RPLC t_(R)=6.03 min (>90%), 220 nm (MethodB-10 min); ESI/MS m/e 516.3 (M⁺+H, C₂₉H₃₃N₅O₂S).

Preparation of 1-(4-Cyanobenzyl )piperazine

To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL)was added 1 M HCl-EtOH (60 mL) dropwise over 1 h and the suspension washeated to 70° C. for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1equiv) was added and the reaction was heated to reflux for 16 h. Aftercooling the solvent was removed by rotary evaporation and the residuewas partitioned between CH₂Cl₂ (70 mL) and 2N aqueous KOH (70 mL) andthe combined organic phase was washed with saturated aqueous NaCl (100mL) and dried (MgSO₄). Chromatography (SiO₂, 20% CH₃OH-5% Et₃N-CH₂Cl₂)afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43%) asan amber oil.

General Alkylation of 1-(4-Cyanobenzyl )piperazine for Examples 204 and205

A solution of 1-(4-cyanobenzyl)piperazine (150 mg, 0.745 mmol) wastreated with alkylating reagent (0.745 mmol, 1 equiv) and ¹Pr₂NEt (156mL, 0.894 mmol, 1.2 equiv). The reaction mixture was heated to 70° C.and stirred by vortex for 16 h. After cooling, the reaction mixture wassubjected directly to chromatography (SiO₂, 3-7% CH₃OH—CH₂Cl₂, gradientelution) to afford the desired N,N-dialkylated piperazine (11-77%).

Example 204

Compound No. 9 (142 mg, 48%) was prepared from1-(4-cyanobenzyl)piperazine (150 mg, 0.745 mmol) and 3,3-diphenylpropylmethanesulfonate (216 mg, 0.745 mmol, 1 equiv) employing generalalkylation procedure. RPLC t_(R)=6.47 min (>95%), 220 nm (Method B);ESI/MS m/e 396.2 (M⁺+H, C₂₇H₂₉N₃).

Example 205

Compound No. 1 (166 mg, 53%) was prepared from1-(4-cyanobenzyl)homopiperazine (150 mg, 0.745 mmol) and4-bromo-2,2-diphenylbutyronltrile (224 mg, 0.745 mmol) employing generalalkylation procedure. RPLC t_(R)=6.82 min (>95%), 220 nm (Method B);ESI/MS m/e 422.3 (M⁺+H, C₂₈H₂₈N₄).

General Preparation of Hydrazide Alkylating Agents

The hydrazide starting material (7.93 mmol) was dissolved in CH₃CN (20mL) and treated with chloroacetyl chloride (0.95 mL, 11.93 mmol, 1.5equiv) and Et₃N (1.11 mL, 7.96 mmol, 1.02 equiv). The mixture wasstirred at 25° C. for 16 h and concentrated, The residue was dissolvedin EtOAc (300 mL), washed with 1N aqueous HCl (10 mL) saturated aqueousNaCl (20 mL), dried (MgSO₄), and concentrated in vacuo. The desiredcompound was isolated by trituration with EtOAc, followed by washingwith hexane or chromatography (SiO₂). General alkylation procedure forExample 163-194 was then used to afford the desired homopiperazineanalogs,

Example 206

1-Benzoyl-2-(chloroacetyl)hydrazine (850 mg, 54%) was prepared frombenzhydrazide (1.00 g, 7.34 mmol) and chloroacetyl chloride (0.58 mL,7.34 mmol, 1 equiv) using general procedure. Compound No. 78 (300 mg,51%) was prepared from 1-(3,3-diphenyipropyl)homopiperazine (100 mg,0.34 mmol) and 1-benzoyl-2-(chloroacetylhydrazine (80 mg, 0.38 mmol)employing general alkylation procedure. TLC R_(f)=0.44 (10%CH₃OH—CH₂Cl₂), RPLC t_(R)=5.85 min (>85%), 220 nm (Method B): ESI/MS m/e471.3 (M⁺+H, C₂₉H₃₄N₄O₂).

Example 207

1-(Chloroacetyl)-2-(phenylacetyl)hydrazine (1.24 g, 82%) was preparedfrom phenylacetohydrazide (1.00 g, 6.66 mmol) and chloroacetyl chloride(0.53 mL, 6.66 mmol, 1 equiv) using general procedure. Compound No. 79(71 mg, 43%) was prepared from 1-(3,3-diphenylpropyl)homopiperazine (100mg, 0.34 mmol) and 1-(chloroacetyl)-2-(phenylacetyl)hydrazine (85 mg,0.38 mmol) employing general alkylation procedure. TLC R_(f)=0.40 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.02 min (>85%), 220 nm (Method 8): ESI/MS m/e485.5 (M⁺+H, C₃₀H₃₆N₄O₂).

Example 208

1-(2-Furoyl)-2-(chloroacetyl)hydrazine (1.21 g, 75%) was prepared from2-furoic acid hydrazide (1.06 g, 7.93 mmol) and chloroacetyl chloride(0.95 mL, 11.9 mmol, 1.5 equiv) using general procedure. Compound No.251 (63 mg, 40%) was prepared from 1-(3,3-diphenylpropyl)homopiperazine(100 mg, 0.34 mmol) and 1-(2-furoyl)-2-(chloroacetyl)hydrazine (76 mg,0.38 mmol) employing general alkylation procedure. TLC R_(f)=0.42 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.60 min (>85%), 220 nm (Method B): ESI/MS m/e461.3 (M⁺+H, C₂₇H₃₂N₄O₃).

Example 209

1-(2-Thiophenecarbonyl)-2-(chloroacetyl)hydrazine (1.14 g, 74%) wasprepared from 2-thiophenecarbohydrazide (1.00 g, 7.03 mmol) andchloroacetyl chloride (0.86 mL, 10.6 mmol, 1.5 equiv) using generalprocedure. Compound No. 252 (88 mg, 54%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(2-Thiophenecarbonyl )-2-(chloroacetyl)hydrazine (82 mg, 0.38 mmol)employing general alkylation procedure. TLC R_(f)=0.47 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.92 min (>85%), 220 nm (Method B); ESI/MS m/e477.3 (M⁺+H, C₂₇H₃₂N₄O₂S).

Example 210

1-(Diphenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (1.30 g, 65%) wasprepared from 4,4-dlphenylsemicarbazide (1.5 g, 6.60 mmol) andchloroacetyl chloride (0.79 mL, 9.92 mmol, 1.5 equiv) using generalprocedure. Compound No. 297 (46 mg, 24%) was prepared from1-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and1-(diphenylcarbamoyl)-4(2-chloroacetyl)semicarbazide (114 mg, 0.38 mmol)employing general alkylation procedure. TLC R_(f)=0.44 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.55 min (>85%), 220 nm (Method B): ESI/MS m/e562.5 (M⁺+H, C₃₅H₃₉N₅O₂).

Example 211

1-(Phenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (1.19 g, 67%) wasprepared from 4-phenylsemicarbazide (1.00 g, 6.62 mmol) and chloroacetylchloride (0.79 mL, 9.92 mmol) using general procedure. Compound No. 82(33 mg, 20%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine(100 mg, 0.34 mmol) and1-(phenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (85 mg, 0.37 mmol)employing general alkylation procedure. TLC R_(f)=0.41 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.96 min (>85%), 220 nm (Method B); ESI/MS m/e486.4 (M⁺+H, C₂₉H₃₅N₅O₂).

Example 212

1-(Ethylcarbamoyl)-2-(chloroacetyl)hydrazjne (1.31 g, 76%) was preparedfrom ethyl carbazate (1.00 g, 9.61 mmol) and chloroacetyl chloride (1.15mL, 10.16 mmol, 1 equiv) using general procedure. Compound No. 224 (81mg, 54%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100mg, 0.34 mmol) and 1-(ethylcarbamoyl)-2-(chloroacetyl)hydrazine (68 mg,0.37 mmol) employing general alkylation procedure. TLC R_(f)=0.44 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.91 min (>85%), 220 nm (Method B); ESI/MS m/e439.3 (M⁺+H, C₃₆H₃₆N₄O₃).

Example 213

1-(4-Nitrobenzoyl)-2-(chloroacetyl)hydrazine was prepared from⁴-nitrobenzhydrazide (1.00 g, 5.52 mmol) and chloroacetyl chloride (0.66mL, 8.29 mmol) using general procedure. Trituration from EtOAc gave thehydrazine in quantitative yield, which was used without furtherpurification. Compound No. 86 (56 mg, 32%) was prepared from1-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and1-(4-nitrobenzoyl)-2-(chlaroacetyllhydrazine (96 mg, 0.37 mmol)employing general alkylation procedure. TLC R_(f)=0.46 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.56 min (>85%), 220 nm (Method A): ESI/MS m/e516.3 (M⁺+H, C₂₉H₃₃N₅O₄).

Example 214

1-(Toluoyl)-2-(chloroacetyl)hydrazine was prepared from 4-toluichydrazide (1.00 g, 6.66 mmol) and chloroacetyl chloride (0.80 mL, 9.99mmol) using general procedure. Trituration from EtOAc gave the hydrazinein quantitative yield, which was used without further purification.Compound No. 87 (61 mg, 37%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(toluoyl)-2-(chloroacetyl)hydrazine (74 mg, 0.37 mmol) employinggeneral alkylation procedure. TLC R_(f)=0.44 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.51 min (>85%), 220 nm (Method A): ESI/MS m/e 485.4 (M⁺+H,C₃₆H₃₆N₄O₂).

Example 215

1-(4-Hydroxybenzoyl)-2-(chloroacetyl)hydrazine was prepared from4-hydroxybenzhydrazide (1.00 g, 6.57 mmol) and chloroacetyl chloride(0.79 mL, 9.92 mmol) using general procedure. Trituration from EtOAcgave the hydrazine in quantitative yield, which was used without furtherpurification. Compound No. 89 (71 mg, 43%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(4-hydroxy benzoyl)-2-(chloroacetyl)hydrazine (85 mg, 0.37 mmol)employing general alkylation procedure. RPLC t_(R)=6.21 min (>85%), 220nm (Method B-10 min); ESI/MS m/e 487.3 (M⁺+H, C₂₉H₃₄N₄O₃).

Example 216

1-(2-Nitrobenzoyl)-2-(chloroacetyl)hydrazine (0.579 g, 41%) was preparedfrom 2-nitrobenzhydrazide (1.00 g, 5.52 mol) and chloroacetyl chloride(0.66 mL, 8.83 mmol) using general procedure. Compound No. 90 (82 mg,47%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100 mg,0.34 mmol) and 1-(2-nitrobenzoyl)-2-(chloroacetyl)hydrazine (96 mg, 0.37mmol) employing general alkylation procedure. TLC R_(f)=0.40 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.04 min (>851), 220 nm (Method B): ESI/MS m/e516.1 (M⁺+H, C₂₉H₃₃N₅O₄).

Example 217

1-(4-Methoxybenzoyl)-2-(chloroacetyl)hydrazine (1.783 g, 54%) wasprepared from 4-methoxybenzhydrazide (1.00 g, 6.00 mmol) andchloroacetyl chloride (0.72 mL, 9.00 mmol) using general procedure.Compound No. 92 (63 mg, 51%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(4-methoxybenzoyl)-2-(chloroacetyl)hydrazine (91 mg, 0.37 mmol)employing general alkylation procedure. TLC R_(f)=0.52 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.46 min (>85%), 220 nm (Method A); ESI/MS m/e501.1 (M⁺+H, C₃₀H₃₆N₄O₃).

Example 218

1-(Nicotinoyl)-2-(chloroacetyl)hydrazine (1.29 g, 83%) was prepared fromnicotinohydrazide (1.00 g , 7.29 mmol) and chloroacetyl chloride (0.87mL, 10.94 mmol) using general procedure. Compound No. 254 (100 mg, 66%)was prepared from 1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34mmol) and 1-(nicotinoyl)-2-(chloroacetyl)hydrazine (87 mg, 0.41 mmol)employing general alkylation procedure. TLC R_(f)=0.12 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=5.61 min (93%), 220 nm (Method B); ESI/MS m/e472.3. (M⁺+H, C₂₈H₃₃N₅O₂).

Example 219

1-(2-Benzo[b]thiophenecarbonyl)-2-(chloroacetyl)hydrazine (0.578 g, 94%)was prepared from (2-benzo[b]thiophenecarbonyl)hydrazine (0.50 g, 2.60mmol) and chloroacetyl chloride (0.31 mL, 3,90 mmol) using generalprocedure. Compound No. 255 (73 mg, 41%) was prepared from1-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and1-(2-benzo[b]thiophenecarbonyl)-2-(chloroacetyl)hydrazine (88 mg, 0.37mmol) employing general alkylation procedure. TLC R_(f)=0.26 (10%CH₃OH—CH₂Cl₂)); RPLC t_(R)=6.96 min (>85%), 220 nm (Method B); ESI/MSm/e 527.3 (M⁺+H, C₃₃H₃₄N₄O₂S).

Example 220

1-(4-Bromobenzoyl)-2-(chloroacetyl)hydrazine (0.886 g, 73%) was preparedfrom 4-bromobenzhydrazide (1.00 g, 4.64 mmol) and chloroacetyl chloride(0.55 mL, 6.90 mmol) using general procedure. Compound No.98 (143 mg,76%) was prepared from 1-(3,3-diphenylpropyl)homopiperazine (100 mg,0.34 mmol) and 1-(4-bromobenzoyl)-2-(chloroacetyl)hydrazine (98 mg, 0.37mmol) employing general alkylatlon procedure. TLC R_(f)=0.50 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.76 min (>85%), 220 nm (Method B); ESI/MS m/e551.0 (M⁺+H, C₂₉H₃₃N₄O₂Br).

Preparation of Sodium [4-(3,3-Diphenylpropyl)homopiperazine-1-yl]acetate

1-(3,3-Diphenylpropyl)homopiperazine (2.0 g, 6.79 mmol) was dissolved inCH₃CN (60 mL) and treated with methyl bromoacetate (1.56 g, 10.18 mmol)and Et₃N (1.42 mL, 10.18 mmol). The mixture was refluxed for 18 h andsubsequently concentrated in vacuo. The residue was subjected to flashsilica gel column chromatography (eluent: CH₂Cl₂/MeOH, 96/4, v/v) togive Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (1.93 g)in 78% yield, TLC R_(f)=0.53 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=4.71 min(>85%), 220 nm (Method A); ESI/MS m/e 367.1 (M⁺+H, C₂₃H₃₀N₂O₂).

Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.327 g, 0.89mmol) was dissolved in a mixture of dioxane (3.1 mL). MeOH (1.1 mL) and4N NaOH (0.22 mL). After stirring for 30 min. 5 more drops of 4N NaOHwere added and stirring was, continued until hydrolysis of the methylester was complete. The mixture was concentrated in vacuo and theresidue subjected to flash silica gel column chromatography (eluent:CH₂Cl₂/MeOH, 1/1, v/v) to give sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.278 g) in 88%yield, TLC R_(f)=0.22 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=1.98 min (>85%),220 nm (Method B); ESI/MS m/e 353.3 (M⁺+H, C₂₂H₂₉N₂O₂).

General Procedure for Coupling to Sodium[4-(3,3-Diphenylpropyl)homopiperazine-1-yl]acetate for Examples 221-253

Sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08mmol) was suspended in dry CH₂Cl₂ (1 mL) and HOBt (12 mg, 0.089 mmol)and the amine, hydrazide or amino acid (0.88 mmol) were added. Aftercooling the mixture to 0° C., EDCI (30 mg, 0.10 mmol) was added, the pHadjusted to 7-8 with Et₃N and the mixture was stirred for 15 min at 0°C. and 16 h at rt. Concentration in vacuo of the mixture gave a residuewhich was not worked up but purified directly by HPLC.

Example 221

Compound No. 270 (55.6 mg, 70%) was prepared from sodium sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (53.6 mg, 0.15 mmol)and dihexylamine (39 mL, 0.167 mmol) employing general couplingprocedure. TLC R_(f)=0.46 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=8.27 min(>85%), 220 nm (Method B); ESI/MS m/e 520.6 (M⁺+H, C₃₄H₅₃N₃O).

Example 222

Compound No. 83 (30 mg, 39%) was prepared sodium sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (60.2 mg, 0.17 mmol)and benzylhydrazine dihydrochloride (40 mg, 0.205 mmol) employinggeneral coupling procedure. TLC R_(f)=0.39 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.16 min (>85%), 220 nm (Method B); ESI/MS m/e 457.3 (M⁺+H,C₂₉H₃₆N₄O).

Example 223

Methyl 2-benzoylhydrazinoacetate (0.418 g, 27%) was prepared frombenzhydrazide (1.00 g, 7.34 mmol) and methyl bromoacetate (0.76 mL, 80.3mmol) employing general procedure. Compound No. 84 (37 mg, 44%) wasprepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate(56 mg, 0.158 mmol) and methyl 2-benzoylhydrazinoacetate (36 mg, 0.17mmol) employing general coupling procedure. TLC R_(f)=0.49 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.21 min (>85%), 220 nm (Method B): ESI/MS m/e543.1 (M⁺+H, C₃₂H₃₈N₄O₄).

Example 224

Compound No. 85 (59 mg, 75%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1yl]acetate (62 mg, 0.166 mmol)and 2-aminoacetophenone hydrochloride (33 mg, 0.195 mmol) employinggeneral coupling procedure. TLC R_(f)=0.40 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.51 min (>85%), 220 nm (Method A): ESI/MS m/e 470.3 (M⁺+H,C₃₀H₃₅N₃O₂).

Example 225

Compound No. 88 (41 mg, 58%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (50 mg, 0.14 mmol)and 4-chlorobenzhydrazide (27 mg, 0.156 mmol) employing general couplingprocedure. RPLC t_(R)=5.71 min (>85%), 220 nm (Method A): ESI/MS m/e505.2 (M⁺+H, C₂₉H₃₃N₄O₂Cl).

Example 226

Compound No. 91 (55 mg, 68%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (60 mg, 0.16 mmol)and 2-amino-4′-methoxyacetophenone hydrochloride (36 mg, 0.176 mmol)employing general coupling procedure. TLC R_(f)=0.55 (10% CH₃OH—CH₂Cl₂);RPLC t_(R)=6.50 min (>85%), 220 nm (Method B); ESI/MS m/e 500.2 (M⁺+H,C₃₁H₃₇N₃O₃).

Example 227

Compound No. 271 (51 mg, 73%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (60 mg, 0.16 mmol)and dipropylamine (24 mL, 0.176 mmol) employing general couplingprocedure. TLC R_(f)=0.56 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.51 min(>85%), 220 nm (Method A); ESI/MS m/e 436.3 (M⁺+H, C₂₈H₄₁N₃O).

Example 228

Compound No. 186 (34 mg, 23%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (100 mg, 0.267 mmol)and benzenesulfonohydrazide (54 mg, 0.31 mmol) employing generalcoupling procedure. TLC R_(f)=0.47 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.31min (87%), 220 nm (Method B); ESI/MS m/e 507.5 (M⁺+H, C₂₈H₃₄N₄O₃S).

Example 229

Compound No. 93 (79 mg, 81%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (75 mg, 0.20 mmol)and 4-aminobenzhydrazide (34 mg, 0.22 mmol) employing general couplingprocedure. TLC R_(f)=0.26 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.61 min(>85%), 220 nm (Method B); ESI/MS m/e 486.3 (M⁺+H, C₂₉H₃₅N₅O₂).

Example 230

Compound No. 94 (24.4 mg, 17%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (100 mg, 0.267 mmol)and 4-methoxybenzenesulfonohydrazide (59.4 mg, 0.29 mmol) employinggeneral coupling procedure; TLC R_(f)=0.45 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.71 min (>85%), 220 nm (Method B); ESI/MS m/e 537.3 (M⁺+H,C₂₉H₃₆N₄O₄S).

Example 231

Compound No. 95 (27.9 mg, 20%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (100 mg, 0.267 mmol)and p-toluenesulfonohydrazide (55 mg, 0.295 mmol) employing generalcoupling procedure. TLC R_(f)=0.52 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.91min (>85%), 220 nm (Method B); ESI/MS m/e 521.3 (M⁺+H, C₂₉H₃₆N₄O₃S).

Example 232

Compound No. 272 (34 mg, 65%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and glycine methyl ester hydrochloride (10.6 mg, 0.084 mmol) employinggeneral coupling procedure. TLC R_(f)=0.42 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.96 min (>851), 220 nm (Method B); ESI/MS m/e 424.3 (M⁺+H,C₂₅H₃₃N₃O₃).

Example 233

Compound No. 273 (37 mg, 72%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and glycinamide hydrochloride (9.3 mg, 0.084 mmol) employing generalcoupling procedure. TLC R_(f)=0.32 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.76min (>85%), 220 nm (Method B); ESI/MS m/e 409.3 (M⁺+H, C₂₄H₃₂N₄O₂).

Example 234

Compound No. 274 (24 mg, 47%) was prepared sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and glycine tert-butyl ester hydrochloride (14.1 mg, 0.084 mmol)employing general coupling procedure. This compound was purified bydiluting with CH₂C₂, washing with NaHCO₃, brine, drying (MgSO₄),filtering and evaporating off the solvent in vacuo. Final purificationby silica gel column chromatography. TLC R_(f)=0.41 (10% CH₃OH—CH₂Cl₂);RPLC t_(R)=6.56 min (>85%), 220 nm (Method B): ESI/MS m/e 466.5 (M⁺+H,C₂₈H₃₉N₃O₃).

Example 235

Compound No. 275 (26.9 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and (D)-(−)-2-phenylglycinol (13.2 mg, 0.096 mmol) employing generalcoupling procedure. TLC R_(f)=0.42 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.21min (>85%), 220 nm (Method B); ESI/MS m/e 472.0 (M⁺+H, C₃₀H₃₇N₃O₂).

Example 236

Compound No. 226 (27.0 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and (1S,2R)-(−)-cis-1-amino-2-indanol (14.3 mg, 0.096 mmol) employinggeneral coupling procedure. TLC R_(f)=0.42 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.36 min (>85%), 220 nm (Method B); ESI/MS m/e 484.0 (M⁺+H,C₃₂H₃₇N₃O₂).

Example 237

Compound No. 276 (24.9 mg, 20%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and (1R, 2S)-(+)-cis-1-amino-2-indanol (14.3 mg, 0.096 mmol) employinggeneral coupling procedure. TLC R_(f)=0.42 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.26 min (>85%), 220 nm (Method B); ESI/MS m/e 484.0 (M⁺+H,C₃₁H₃₇N₃O₂).

Example 238

Compound No. 277 (29.9 mg, 43%) was prepared sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and dl-octopamine hydrochloride (18.2 mg, 0.096 mmol) employing generalcoupling procedure. TLC R_(f)=0.24 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.76min (95%), 220 nm (Method B); ESI/MS m/e 488.0 (M⁺ 30 H, C₃₀H₃₇N₃O₂).

Example 239

Compound No. 278 (28.3 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and dl-norphenylephrine hydrochloride (18.2 mg, 0.38 mmol) employinggeneral coupling procedure. TLC R_(f)=0.24 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.91 min (>85%), 220 nm (Method B); ESI/MS m/e 488.0 (M⁺+H,C₃₀H₃₇N₃O₃).

Example 240

Compound No. 279 (27.7 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and (1S,2S)-(+)-2-amino-3-methoxy-1-phenyl-1-propanol (17.4 mg, 0.096mmol) employing general coupling procedure. TLC R_(f)=0.46 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=6.36 min (>85%), 220 nm (Method B); ESI/MS m/e516.0 (M⁺+H, C₃₂H₄₁N₃O₃).

Example 241

Compound No. 280 (29.9 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and norephedrine hydrochloride (18.0 mg, 0.096 mmol) employing generalcoupling procedure. TLC R_(f)=0.46 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.06min (>85%), 220 nm (Method B); ESI/MS m/e 486.3 (M⁺+H, C₃₁H₃₉N₃O₂).

Example 242

Compound No. 281 (22.4 mg, 20%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and 2-amino-1-phenyrethanol (16.2 mg, 0.118 mmol) employing generalcoupling procedure. TLC R_(f)=0.53 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.11min (>85%), 220 nm (Method B); ESI/MS m/e 472.3 (M⁺+H, C₃₀H₃₇N₃O₂).

Example 243

Compound No. 298 (26.9 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and 2-amino-1,3-propanediol (11.0 mg, 0.121 mmol) employing generalcoupling procedure. TLC R_(f)=0.16 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.51min (>85%), 220 nm (Method B); ESI/MS m/e 426.0 (M⁺+H, C₂₅H₃₅N₃O₃).

Example 244

Compound No. 282 (26.9 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and L-phenylalaninol (17.8 mg, 0.118 mmol) employing general couplingprocedure. TLC R_(f)=0.53 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.31 min(>85%), 220 nm (Method B); ESI/MS m/e 486.3 (M⁺+H, C₃₂H₃₈N₄O₂).

Example 245

Compound No. 283 (27.0 mg, 46%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-phenylalaninamide hydrochloride (19.3 mg, 0.096 mmol) employinggeneral coupling procedure. TLC R_(f)=0.25 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=2.16 min (>85%), 220 nm (Method B); ESI/MS m/e 499.4 (M⁺+H,C₃₁H₃₈N₄O₂).

Example 246

Compound No. 284 (24 mg, 42%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-aspartic acid dimethyl ester hydrochloride (19.0 mg, 0.096 mmol)employing general coupling procedure. TLC R_(f)=0.46 (10% CH₃OH—CH₂C₂);RPLC t_(R)=2.16 min (>85%), 220 nm (Method B -); ESI/MS m/e 496.4 (M⁺+H,C₂₈H₃₇N₃O₅).

Example 247

Compound No. 285 (32.4 mg, 49%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-phenylalanine benzyl ester p-toluenesulfonic acid salt (34.3 mg,0.08 mmol) employing general coupling procedure. TLC R_(f)=0.53 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=2.53 min (>85%), 220 nm (Method B); ESI/MS m/e590.6 (M⁺+H, C₃₈H₄₃N₃O₃).

Example 248

Compound No. 286 (22.5 mg, 40%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-leucine methyl ester hydrochloride (17.5 mg, 0.096 mmol)employing general coupling procedure. , TLC R_(f)=0.53 (10%CH₃OH—CH₂Cl₂); RPLC t_(R)=2.21 min (>85%), 220 nm (Method B); ESI/MS m/e480.5 (M⁺+H, C₂₉H₄₁N₃O₃).

Example 249

Compound No. 287 (23 mg, 20%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, o.08 mmol)and DL-tyrosine methyl ester hydrochloride (22.3.0 mg, 0.096 mmol)employing general coupling procedure. RPLC t_(R)=2.01 min (>85%), 220 nm(Method B); ESI/MS m/e 530.2 (M⁺+H, C₃₂H₃₉N₃O₄).

Example 250

Compound No. 288 (23.8 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-methionine methyl ester hydrochloride (19.2 mg, 0.096 mmol)employing general coupling procedure. RPLC t_(R)=2.01 min (>85%), 220 nm(Method B); ESI/MS m/e 498.2 (M⁺+H, C₂₈H₃₉N₃O₃S).

Example 251

Compound No. 289 (21.6 mg, 30%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-Tryptophan methyl ester hydrochloride (24.5 mg, 0.096 mmol)employing general coupling procedure, RPLC t_(R)=2.27 min (>85%), 220 nm(Method B); ESI/MS m/e 553.4 (M⁺+H, C₃₄H₄₁N₃O₂).

Example 252

Compound No. 299 (20.9 mg, 43%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and (1S,2R)-(+)-2-amino-1,2-diphenylethanol (20.5 mg, 0.096 mmol)employing general coupling procedure. RPLC t_(R)=2.12 min (>85%), 220 nm(Method B); ESI/MS m/e 548.4 (M⁺+H, C₃₆H₄₁N₃O₂).

Example 253

Compound No. 291 (23.8 mg, 41%) was prepared from sodium[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol)and DL-methionine methyl ester hydrochloride (19.2 mg, 0.096 mmol)employing general coupling procedure. RPLC t_(R)=2.21 min (>85%), 220 nm(Method B); ESI/MS m/e 484.4 (M⁺+H, C₂₇H₃₇N₃O₃S).

Preparation of [4-(3,3-Dlphenylpropyl)-1-homopiperazinyl]acetobydrazide

Methyl [4-(3,3-diphenylpropyl)-1-homopiperazinyl]acetate (0.607 g, 1.66mmol) was dissolved in ethanol (20 mL) and hydrazine hydrate (1 mL) wasadded, The mixture was refluxed for 19 h and subsequently concentratedin vacuo. The residue was taken up in EtOAc. washed with brine, dried(MgSO₄) and concentrated in vacuo to afford the title compound as an oil(0.547 g) in 90% yield, TLC R_(f)=0.35 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=1.93 min (>85%), 220 nm (Method B); ESI/MS m/e 367.1 (M⁺+H,C₂₂H₃₀N₄O).

General Coupling Procedure for(4-(3,3-Diphenyipropyl)-1-hamopiperazinyl]acatohydrazide for Examples254-256

[4-(3,3-Diphenylpropyl)-1-homopiperazinyl]acetohydrazide (60.5 mg, 0.165mmol) was dissolved in dry CH₂Cl₂ (2 mL) and CH₃CN (0.5 mL). Pyridine(19 mL, 0.23 mmol) and the sulfonyl chloride (0.195 mmol) were added andthe mixture was stirred at room temperature for 16 h. Afterconcentration of the mixture in vacuo, flash silica gel columnchromatography was used to isolate the desired product.

Example 254

Compound No. 96 (69 mg, 70%) was prepared from[4-(3,3-Diphenylpropyl)-1-homopiperazinyllacetohydrazide (65 mg, 0.177mmol) and N-acetylsulfanilyl chloride (46 mg, 0.195 mmol) employinggeneral coupling procedure. TLC R_(f)=0.35 (10% CH₃OH—CH₂Cl₂); RPLCt_(R)=6.36 min (>851), 220 nm (Method B); ESI/MS m/e 564.3 (M⁺+H,C₃₀H₃₇N₅O₄S).

Example 255

Compound No. 97 (63.5 mg, 71%) was prepared from[4-(3,3-Diphenylpropyl)-1-homopiperazinyl]acetohydrazide (60.5 mg, 0.165mmol) and 4-chlorobenzenesulfonyl chloride (38.3 mg, 0.181 mmol)employing general coupling procedure. RPLC t_(R)=7.01 min (>85%), 220 nm(Method B); ESI/MS m/e 541.3 (M⁺+H, C₂₈H₃₃N₄O₃SCl).

Example 256

Compound No. 256 (40 mg, 53%) was prepared from[4-(3,3-Diphenylpropyl)-1-homopiperazinyl]acetohydrazide (55 mg, 0.15mmol) and 2-thiophenesulfonyl chloride (30 mg, 0.164 mmol) employinggeneral coupling procedure., RPLC t_(R)=6.61 min (>85%), 220 nm (MethodB); ESI/MS m/e 513.3 (M⁺+H, C₂₆H₃₂N₄O₃S₂).

Example 257

Compound No. 99 (55 mg, 64%) was prepared by dissolving[4-(3,3-Diphenylpropyl)-1-homopiperazinyl]acetohydrazide (51 mg, 0.139mmol) in dry CH₂Cl₂ (2 mL) and adding HOBt (21 mg, 0.155 mmol) and4-(methylsulfonyl)benzoic acid (29 mg, 0.146 mmol). This mixture wascooled (0° C.) and treatede with EDCI (45 mg, 0.151 mmol) followed byEt₃N such that the pH was around 8. After stirring for 16 h at roomtemperature, the mixture was diluted with CH₂Cl₂, washed with saturatedNaHCO₃, brine, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was applied to silica gel column chromatography (eluent:gradient of 96/4 to 94/6 CH₂Cl₂/MeOH, v/v) to afford the desiredcompound, TLC R_(f)=0.45 (10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.06 min (>85%),220 nm (Method B); ESI/MS m/e 549.3 (M⁺+H, C₃₈H₃₆N₄O₄S).

Example 258

Compound No. 100 (45 mg, 64%) was prepared by dissolving[4-(3,3-Diphenylpropyl)-1-homopiperazinyl]acetohydrazide (49 mg, 0.134mmol) in dry CH₂Cl₂ (2 mL) and adding HOBt (20 mg, 0.148 mmol) and4-acetylbenzoic acid (23 mg, 0.14 mmol). This mixture was cooled (0° C.)and treated with EDCI (44 mg, 0.148 mmol) followed by Et₃N such that thepH was around 8. After stirring for 16 h at room temperature, themixture was diluted with CH₂Cl₂, washed with saturated NaHCO₃, brine,dried (MgSO₄), filtered and concentrated in vacuo. The residue wasapplied to silica gel column chromatography (eluent: gradient of 96/4 to94/6 CH₂Cl₂/MeOH, v/v) to afford the desired compound, TLC R_(f)=0.46(10% CH₃OH—CH₂Cl₂); RPLC t_(R)=6.26 min (>85%), 220 nm (Method B).ESI/MS m/e 513.3 (M⁺+H, C₃₁H₃₆N₄O₃).

Example 259

Compound No. 290 (6.6 mg, 64%) was prepared by treatment of Compound No.286 (10.5 mg, 0.015 mmol) with 0.44 mL of 0.25 N LiOH (MeOH/H₂O, 3/1,v/v) at room temperature for 16 h. After acidifying the reaction mixturewith TFA and evaporating off the solvents, the residue was purifiedusing a small C-18 column (eluent: water followed by MeOH), RPLCt_(R)=2.28 min (>85%), 220 nm (Method B); ESI/MS m/e 466.4 (M⁺+H,C₂₈H₃₉N₃O₃).

Example 260

Compound No. 292 (6.0 mg, 64%) was prepared by treatment of Compound No.289 (9.6 mg, 0.0123 mmol) with 0.35 mL of 0.25 N LiOH (MeOH/H₂O, 3/1,v/v) at room temperature for 16 h. After acidifying the reaction mixturewith TFA and evaporating off the solvents, the residue was purifiedusing a small C-18 column (eluent: water followed by MeOH), RPLCt_(R)=2.41 min (>85%), 220 nm (Method B); ESI/MS m/e 539.3 (M⁺+H,C₃₃H₃₈N₄O₃).

Example 261 Preparation of Compound No. 69

A solution of 1-[4-(methylsulfonyl )benzyl]homopiperazine (314 mg, 1.17mmol) in CH₃CN (50 mL) was treated sequentially with3-[4-(tert-butoxycarbonyl)phenyl]-3-phenylpropyl methanesulfonate (456mg, 1.17 mmol, 1 equiv) and Na₂CO₃ (124 mg, 1.17 mmol, 1 equiv). Thereaction mixture was heated to 70° C. for 16 h, cooled to 25° C.filtered and concentrated. Chromatography (SiO₂, 2×20 cm, 5%CH₃OH—CH₂Cl₂) afforded the desired material (346 mg, 53%) RPLCt_(R)=7.63 min (>90%), 220 nm (Method A); ESI/MS m/e 563.2 (M⁺+H,C₃₃H₄₂N₂O₄S).

Example 262 Preparation of Compound No. 72 and 73

A solution of compound No. 69 (278 mg, 0.494 mmol) in CH₃OH (2 mL) wastreated with a 1.0 M solution of HCl-Et₂O (5 mL) and stirred at 25° C.for 1 h. Concentration and chromatography (SiO₂, 2×20 cm, 5%CH₃OH—CH₂Cl₂ to CH₃OH, gradient elution) afforded the compound No. 72(132 mg, 51%) and compound No. 73 (88 mg, 35%). Compound No. 72; RPLCt_(R)=4.78 min (>90%), 220 nm (Method A); ESI/MS m/e 521.2 (M⁺+H,C₃₀H₃₆N₂O₄S). For compound No. 73; RPLC t_(R)=4.08 min (>95%), 220 nm(Method A); ESI/MS m/e 507.2 (M⁺+H, C₂₉H₃₄N₂O₄S).

Example 263 Preparation of1-(tert-Butyloxycarbonyl)-4-(3-hydroxy-3-(3-hydrozyphenyl)-3-phenylpropyl]homopiperazine(Compound No. 294)

1. A solution of di-tert-butyl dicarbonate (25 g, 115 mmol.) in CH₂Cl₂(100 mL) was added over a period of 20 min to a solution ofhomopiperazine (57 g, 5.0 equiv) in CH₂Cl₂ (200 mL). The reactionmixture was stirred at room temperature for 3 days. H₂O (150 mL) wasadded to the reaction mixture and the mixture was extracted with CH₂Cl₂(2×100 mL). The combined extracts were washed with brine and dried overMgSO₄. The solvent was removed under reduced pressure to afford an oilwhich was purified by simple distillation to give1-(tert-butyloxycarbonyl)homopiperazine: 13.68 g, 59% yield, colorlessoil: The purity was determined by GC/MS (95%), m/e 200.1 (M⁺,C₁₀H₂₀N₂O₂).

2. 3-Chloropropiophenone (7.14 g, 24.4 mmol). K₂CO₃ (8.79 g, 1.50 equiv)and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified1-(tert-butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH₃CN(60 mL). The reaction mixture was stirred at 70° C. for 17 h and thenAcOEt (200 mL) was added to the cooled mixture. The precipitated solidwas removed by filtration and washed with AcOEt (50 mL). The combinedfiltrate was evaporated to afford an oil which was purified by columnchromatography (SiO₂, 0%-20% CH₃CN/AcOEt) to give1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine: 11.27g, 80% yield, pale yellow oil: ¹H NMR (CDCl₃, 300 MHz) δ 1.40-1.65 (m,9H), 1.80-1.95 (m, 2H), 2.65-2.85 (m, 4H), 3.01 (t, 2H, J=6.9 Hz), 3.19(t, 2H, J=6.9 Hz), 3.35-3.55 (m, 4H), 7.47 (t, 2H, J=7.7 Hz), 7.55-7.65(m, 1H), 7.90-8.02 (m, 2H). The purity was determined by RPLC/MS (MethodB). RPLC t_(R)=5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M⁺+H,C₁₉H₂₉N₂O₃).

3. A solution of 3-(tert-butyldimethylsilyloxy)phenylmagnesium bromide[prepared from 3-(tert-butyldimethylsilyloxy)bromobenzene (28.5 g, 99.2mmol) and magnesium turnings (2.30 g, 94.5 mmol) in Et₂O (65 mL) I wasadded at 0° C. to a solution of the purified1-(tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropyl)homopiperazine (11.25g, 33.8 mmol) in dry THF (150 mL). The mixture was warmed to roomtemperature with stirring and the stirring was continued for 3 h.Saturated aqueous NH₄Cl (300 mL) was added to the reaction mixture, themixture was stirred for 15 min and extracted with AcOEt (3×150 mL). Thecombined extracts were washed with brine and dried over MgSO₄. Thesolvent was removed under reduced pressure to afford an oil (31.00 g)which was purified by column chromatography (SiO₂, 3%-25% AcOEt/hexane)to give1-(tert-butyloxycarbonyl)-4-[3-{3-(tert-butyldimethylsilyloxy)phenyl}-3-hydroxy-3-phenylpropyl]homopiperazine: 9.00 g, 49% yield, pale yellow oil; ¹H NMR (CDCl₃, 300 MHz) δ 0.00 (s,6H), 0.81 (s, 9H), 1.32 (s, 9H), 1.4-1.5 (m, 2H), 1.7-1.8 (m, 2H),2.2-2.3 (m, 2H), 2.4-2.55 (m, 4H), 3.25-3.45 (m, 4H), 6.50-6.56 (m, 1H),6.80-6.92 (m, 2H), 6.99-7.10 (m, 2H), 7.11-7.20 (m, 2H), 7.28-7.34 (m,2H), The purity was determined by RPLC/MS (Method A). RPLC t_(R)=7.13min (>95%), 220 nm: ESI/MS m/e 541.3 (M⁺+H, C₃₁H₄₉N₂O₂Si).

4. A solution of tetrabutylammonium fluoride (1.0 M solution in THF, 4.0mL, 4.0 mmol, 1.03 equiv) was added to a solution of the purified1-(tert-butyloxycarbonyl)-4-[3-{3-(tert-butyldimethylsilyloxy)phenyl}-3-hydroxy-3-phenylpropyl]homopiperazine(2.11 g, 3.90 mmol) in THF (35 mL). The mixture was stirred at roomtemperature for 30 min. H₂O (100 mL) was added to the reaction mixtureand the mixture was extracted with AcOEt (3×100 mL). The combinedextracts were washed with brine and dried over MgSO₄. The solvent wasremoved under reduced pressure to afford an oil (3.11 g) which waspurified by column chromatography (SiO₂, 50% ACOEt/hexane) to give1-(tert-butyloxycarbonyl)-4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine(compound No. 294): 1.381 g, 83% yield, colorless oil; ¹H NMR (CDCl₃,300 MHz) δ 1.47 (s, 3H), 1.50 (s, 6H), 1.9-2.1 (m, 2H), 2.45-2.9 (m,8H), 3.3-3.8 (m, 4H), 6.7-7.0 (m, 2H), 7.05-7.28 (m, 2H), 7.3-7.38 (m,2H), 7.42-7.50 (m, 2H). The purity was determined by RPLC/MS (Method A).RPLC t_(R)=5.30 min (>95%), 220 m: ESI/MS m/e 427.3 (M⁺+H, C₂₅H₃₅N₂O₄).

Example 264 Preparation of1-[3-Hydroxy-3-(3-hydrozyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295)

p-Toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol, 4.0 equiv) wasadded to a solution of the purified1-(tert-butyloxycarbonyl)-4-(3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine(Compound No. 294, 1.066 g, 2.50 mmol) in CH₃CN (15 mL)). The reactionmixture was stirred at room temperature for 2.0 h and then. H₂O (50 mL)and CH₃OH (20 mL) were added. Anion exchange resin (11.5 g, DOWEX1×2-200, washed with aqueous NaOH) was added and the mixture was gentlyagitated at room temperature for 5 min. The resin was removed byfiltration and washed with CH₃OH (300 mL). The combined filtrate wasevaporated to afford an oil (1.35 g) which was purified by columnchromatography (SiO₂, 5%->10% CH₃OH, 5% TEA/CH₂Cl₂) to give1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295): 657 mg, 81% yield, colorless oil; ¹H NMR (CDCl₃, 300 MHz) δ1.8-2.0 (m, 2H), 2.35-2.45 (m, 2H), 2.55-2.80 (m, 6H), 3.0-3.15 (m, 4H),6.68-6.75 (m, 1H), 6.82-6.88 (m, 1H), 7.10-7.38 (m, 5H), 7.42-7.52 (m,2H). The purity was determined by RPLC/MS (Method B), RPLC t_(R)=4.27min (>99%), 220 nm; ESI/MS m/e 327.3 (M⁺+H, C₂₀H₂₇N₂O₂).

Example 265 General Alkylation of1-[3-Hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine(Preparation of Compound No. 185)

1-Benzoyl-2-(chloroacetyl)hydrazine (60 mg, 0.281 mmol, 1.2 equiv) andEt₃N (118 mg, 1.17 mmol, 5.0 equiv) were added to a solution of1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 100 mg, 0.306 mmol) in CH₃CN (2.0 mL). The reaction mixture wasstirred at 60-70° C. for 13 h. The solvent was evaporated to afford anoil which was purified by column chromatography (SiO₂, 10% CH₃OH/CH₂Cl₂)to give Compound No. 185: 71 mg, 46% yield, colorless oil; ¹HNMR (CD₃OD,300 MHz) δ 1.85-2.00 (m, 2H), 2.45-2.55 (m, 2H), 2.65-2.75 (m, 2H),2.78-3.00 (m, 8H), 3.36 (s, 2H), 6.62-6.65 (m, 1H), 6.90-6.98 (m, 2H),7.10-7.35 (m, 4H), 7.40-7.65 (m, 5H), 7.88 (d, 2H, J=5.4 Hz). The puritywas determined by RPLC/MS (Method B). RPLC t_(R)=5.08 min (>98%), 220nm; ESI/MS m/e 503.2 (M⁺+H, C₂₉H₃₅N₄O₄).

Example 266

Compound No. 259, di-TFA salt (54.8 mg, 15%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 158 mg, 0.486 mmol) and Maybridge GK02253 (136 mg, 1.2 equiv)employing general alkylation procedure. The product was purified bypreparative RPLC. RPLC t_(R)=4.60 min (>98%), 220 nm (Method A); ESI/MSm/e 523,2 (M⁺+H, C₂₈H₃₅N₄O₄S).

Example 267

Compound No. 227 (20 mg, 35%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 36 mg, 0.11 mmol) and N-(3-bromopropyl)phthalimide (32 mg, 1.1equiv) employing general alkylation procedure. RPLC t_(R)=5.23 min(98%), 220 nm (Method B); ESI/MS m/e 514.3 (M⁺+H, C₃₁H₃₆N₃O₄).

Example 268

Compound No. 227260 (105 mg, 67%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 100 mg, 0.306 mmol) and1-(chloroacetyl)-2-(2-thiophenecarbonl)hydrazine (61 mg, 1.2 equiv)employing general alkylation procedure. RPLC t_(R)=4.95 min (>98%), 220nm (Method B); ESI/MS m/e 509.2 (M⁺+H, C₂₇H₃₃N₄O₄S).

Example 269

Compound No. 261 (94 mg, 53%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 100 mg, 0.306 mmol) and Maybridge RF00404 (79 mg, 1.2 equiv)employing general alkylation procedure. RPLC t_(R)=5.52 min (>98%), 220nm (Method B); ESI/MS m/e 572.2 (M⁺+H, C₂₈H₃₂Cl₂N₅O₄).

Example 270

Compound No. 293 (65 mg, 48%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 100 mg, 0.306 mmol) and N,N-diethylacetamide (150 mg, 4.3equiv) employing general alkylation procedure. RPLC t_(R)=4.68 min(89%), 220 nm (Method B); ESI/MS m/e 440.2 (M⁺+H, C₂₆H₃₈N₃O₃).

Example 271

Compound No. 228 (97 mg, 63%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 100 mg, 0.306 mmol) and1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (230 mg, 4.6 equiv)employing general alkylation procedure. t_(R)=4.98 min (>95%). 220 nm(Method B); ESI/MS m/e 501.1 (M⁺+H, C₃₆H₃₇N₄O₃).

Example 272

Compound No. 229 (60 mg, 63%) was prepared from1-[3-hydroxy-3-[3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 59 mg, 0.182 mmol) and 4-bromo-2-butenyl phenyl sulfone (50 mg,1.0 equiv) employing general alkylation procedure. RPLC t_(R)=5.20 min(>95%), 220 nm (Method B); ESI/MS m/e 521.3 (M⁺+H, C₃₀H₃₇N₂O₄S).

Example 273

Compound No. 262 di-TFA salt (88 mg, 48%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.245 mmol) and1-(chloroacetyl)-2-(5-methylthiophenecarbonl)hydrazine (68 mg, 1.2equiv) employing general alkylation procedure. The Product was purifiedby preparative RPLC. RPLC t_(R)=5.23 min (>98%), 220 nm (Method B);ESI/MS m/e 523.3 (M⁺+H, C₂₈H₃₅N₄O₄S).

Example 274

Compound No. 187 di-TFA salt (19 mg, 9.5%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.245 mmol) and Salor S2.688-4 (88 mg, 1.2 equiv)employing general alkylation procedure. The Product was purified bypreparative RPLC. RPLC t_(R)=5.22 min (>85%), 220 nm (Method B); ESI/MSm/e 589.0 (M⁺+H, C₃₃H₃₇N₂O₆S).

Example 275

Compound No. 189 (26 mg, 42%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 40 mg, 0.123 mmol) and N-(phenacyl)chloroacetamide (32 mg, 1.2equiv) employing general alkylation procedure. RPLC t_(R)=5.73 min(>98%), 220 nm (Method B); ESI/MS m/e 502.3 (M⁺+H, C₃₀H₃₆N₃O₄).

Preparation of 1-[4-(Bromomethyl)benzenesulfonyl]pyrrole

NaH (60% dispersion in mineral oil. 40 mg, 1.0 mmol) was added to asolution of pyrrole (67 mg, 1.0 mmol) in THF (2.0 mL) and the mixturewas stirred at room temperature for 5 min. Then4-(bromomethyl)benzenesulfonyl chloride (269 mg, 1.0 mmol) was added tothe mixture. After stirring at room temperature for additional 10 min,brine (15 mL) was added and the mixture was extracted with AcOEt (40mL×2). The combined extracts were dried over MgSO₄. The solvent wasremoved under reduced pressure to afford an oil which was purified bycolumn chromatography (SiO₂, 10% AcOEt/hexane) to give1-[4-(bromomethyl)benzenesulfonyl]pyrrole: 46 mg, 15% yield, colorlessoil. The purity was determined by GC/MS (>95%), m/e 299 (M⁺,C₁₁H₁₀NO₂BrS).

Example 276

Compound No. 190 (27 mg, 40%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 40 mg, 0.123 mmol) and1-[4-(bromomethyl)benzenesulfonyl]pyrrole (46 mg, 1.24 equiv) employinggeneral alkylation procedure. RPLC t_(R)=5.85 min (>98%), 220 nm (MethodB); ESI/MS m/e 546.3 (M⁺+H, C₃₁H₃₆N₃O₄S).

Example 277

Compound No. 191 (39 mg, 61%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 40 mg, 0.123 mmol) and1-(chloroacetyl)-2-(4-hydroxybenzoyl)hydrazine (28 mg, 1.0 equiv)employing general alkylation procedure. RPLC t_(R)=4.72 min (>95%), 220nm (Method B); ESI/MS m/e 519.3 (M⁺+H, C₂₉H₃₅N₄O₅).

Example 278

Compound No. 194 di-TFA salt (39 mg, 42%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 40 mg, 0.123 mmol) and1-(chloroacetyl)-2-(4-chlorobenzoyl)hydrazine (31 mg, 1.0 equiv)employing general alkylation procedure. The Product was purified bypreparative RPLC. RPLC t_(R)=5.48 min (>95%), 220 nm (Method B); ESI/MSm/e 537.0 (M⁺+H, Cl₂₉H₃₄ClN₄O₅).

Example 279

Compound No. 195 di-TFA salt (30 mg, 33%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 40 mg, 0.123 mmol) and 1-chloroacetyl-4-phenylsemicarbazide (28mg, 1.0 equiv) employing general alkylation procedure. The Product waspurified by preparative RPLC. RPLC t_(R)=5.18 min (>95%)), 220 nm(Method B); ESI/MS m/e 518.3 (M⁺+H, C₂₉H₃₆N₅O₄).

Example 280

Compound No. 231 di-TFA salt (29 mg, 42%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 30 mg, 0.092 mmol) and bromobimane (28 mg, 1.0 equiv) employinggeneral alkylation procedure. The product was purified by preparativeRPLC. RPLC t_(R)=1.87 min (>95%), 220 nm (Method B); ESI/MS m/e 517.4(M⁺+H, C₃₀H₃₇N₄O₄).

Example 281

Compound No. 196 di-TFA salt (33 mg, 46%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 30 mg, 0.092 mmol) and Maybridge CD08063 (29 mg, 1.2 equiv)employing general alkylation procedure. The product was purified bypreparative RPLC. RPLC t_(R)=2.07 min (>98%), 220 nm (Method B); ESI/MSm/e 557.2 (M⁺+H, C₂₈H₃₄ClN₄O₄S).

Example 282

Compound No. 232 tri-TFA salt (6.6 mg; 9.1%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-³-phenylpropyl]homopiperazine (CompoundNo. 295, 30 mg, 0.092 mmol) and Maybridge TB812299 (18 mg, 1.2 equiv)employing general alkylation procedure. The product was purified bypreparative RPLC. RPLC t_(R)=1.48 min (>95%), 220 nm (Method B); ESI/MSm/e 451.2 (M⁺+H, C₂₅H₃₁N₄O₄).

Example 283

Compound No. 296 (16 mg, 18%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 78 mg, 0.24 mmol) and acetyl chloride (19 mg, 1.0 equiv).Acetyl chloride and Et₃N (121 mg, 1.2 mmol, 5.0 equiv) were added to asolution of1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295) in CH₃CN (2.0 mL). The reaction mixture was stirred at roomtemperature for 30 min. saturated aqueous NaHCO₃ (10 mL) was added tothe reaction mixture and the mixture was extracted with AcOEt (3×15 mL).The combined extracts were dried over MgSO₄. The solvent was removedunder reduced pressure to afford an oil which was purified by columnchromatography (SiO₂, 3-10% CH₃OH/CH₂Cl₂) to give1-acetyl-4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine(Compound No. 296): 16 mg, 18% yield, colorless oil: RPLC t_(R)=4.75 min(89%), 220 nm (Method B); ESI/MS m/e 369.3 (M⁺+H, C₂₂H₂₉N₂O₃).

Example 284

Compound No. 263 TFA salt (40 mg, 23%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.25 mmol), 2-(4-chlorobutyryl)thiophene (70 mg, 0.3mmol) and triethylamine (174 mL, 1.25 mmol) employing general alkylationprocedure. TLC R_(f)=0.58 (5% Et₃N-10% CH₃OH—CH₂Cl₂); RPLC t_(R)=4.98min (>85%), 220 nm (Method B); ESI/MS m/e 479.3 (M⁺+H, C₂₈H₃₄N₂O₃S).

Example 285

Compound No. 188 TFA salt (31 mg, 17%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.25 mmol), 3-chloropropyl p-tolyl sulfone (70 mg, 0.3mmol) and triethylamine (174 mL, 1.25 mmol) employing general alkylationprocedure. TLC R_(f)=0.62 (5% Et₃N-10% CH₃OH—CH₂Cl₂); RPLC t_(R)=5.25min (>85%), 220 nm (Method B); ESI/MS m/e 523.3 (M⁺+H, C₃₀H₃₈N₂O₄S).

Example 286

Compound No. 192 TFA salt (34 mg, 19%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.25 mmol), 4-(chloroacetyl)catechol (56 mg, 0.3 mmol)and triethylamnine (174 mL, 1.25 mmol) employing general alkylationprocedure. TLC R_(f)=0.62 (5% Et₃N-10% CH₃OH—CH₂Cl₂), RPLC t_(R)=4.68min (>85%), 220 nm (Method B); ESI/MS m/e 477.3 (M⁺+H, C₂₈H₃₂N₂O₃).

Example 287

Compound No. 230 TFA salt (30 mg, 17%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 80 mg, 0.25 mmol), glycidyl methacrylate (43 mg, 0.3 mmol) andtriethylamine (174 mL, 1.25 mmol) employing general alkylationprocedure. TLC R_(f)=0.6 (5% Et₃N-10% CH₃OH—CH₂Cl₂), RPLC t_(R)=4.95 min(90%), 220 nm (Method B); ESI/MS m/e 469.0 (M⁺+H, C₂₇H₃₆N₂O₅).

Example 288

Compound No. 193 TFA salt (44 mg, 49%) was prepared from1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 50 mg, 0.15 mmol), 2-chloro-4′-fluoro-3′-nitroacetanilide (50mg, 0.12 mmol) and triethylamine (104 mL, 0.75 mmol) employing generalalkylation procedure. TLC R_(f)=0.6 (5% Et₃N-10% CH₃OH—CH₂Cl₂); RPLCt_(R)=5.78 min (>85%), 220 nm (Method B); ESI/MS m/e 523.0 (M⁺+H,C₂₈H₃₁N₄O₅F).

Preparation of 1-[3-(3-Hydroxyphenyl)3phanylprapyl]homopiperazine

1. Trifluoroacetic acid (4.75 mL) was added to a solution of1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (CompoundNo. 295, 60 mg, 0.184 mmol) in CH₂Cl₂ (0.25 mL). The reaction mixturewas stirred at room temperature for 2.5 h. The trifluoroacetic acid wasevaporated to afford1-[3-(3-hydroxyphenyl)-3-phenyl-2-propenyl]homopiperazine as a colorlessoil used without further purification.

2. A solution of1-[3-(3-hydroxyphonyl)-3-phenyl-2-propenyl]homoplperazjme in EtOH (6 mLwas hydrogenated at 1 atm for 1.5 h in the presence of 5% palladium oncharcoal (60 mg) at room temperature. The catalyst was removed byfiltration through Cellte and washed with ETOH (30 mL). The combinedfiltrate was evaporated to give1-[3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (2TFA salt, 100 mg,quantitative) as a white solid used without further purification. RPLCt_(R)=1.62 min (Method B); ESI/MS m/e 311.2 (M⁺+H, C₂₀H₂₇N₂O).

Example 289 General Alkylation of1-[3-(3-Hydroxyphenyl)-3-phenylpropyl]homopiperazine (Preparation ofCompound No. 257)

Maybridge GK02253 (17 mg, 0.074 mmol, 1.2 equiv) and Et₃N (37 mg, 0.37mmol, 6.0 equiv) were added to a solution of1-[3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine 2TFA salt (33 mg,0.061 mmol) in CH₃CN (2.0 mL). The reaction mixture was stirred at 70°C. for 15 h. The solvent was evaporated to afford an oil which waspurified by preparative RPLC to give Compound No. 257 di-TFA salt: 8.0mg, 18% yield, colorless oil. The purity was determined by RPLC/MS. RPLCt_(R)=1.90 min (>95%), 220 nm (Method B); ESI/MS m/e 507.2 (M⁺+H,C₂₀H₃₅N₄O₃S).

Example 290

Compound No. 101 di-TFA salt (6.0 mg, 14%) was prepared from1-[3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine di-TFA salt (33 mg,0.061 mmol) and N-(phenacyl)chloroacetamide (16 mg, 1.2 equiv) employinggeneral alkylation procedure. The product was purified by preparativeRPLC. RPLC t_(R)=1.92 min (>85%), 220 nm (Method B); ESI/MS m/e 486.2(M⁺+H, C₃₀H₃₆N₃O₃).

Preparation of 1-(3,3-Diphenylpropyl)piperazine

1-(tert-butyloxycarbonyl)piperazine (1.00 g, 5.4 mmol) was dissolved inCH₃CN (27 mL) and was treated with 3,3-diphenylpropyl mesylate (1.6 g,5.6 mmol, 1.05 equiv) and ¹PrNEt (1.40 mL, 8.05 mmol, 1.5 equiv). Thereaction mixture was heated to 70° C. for 16 h, cooled and concetrated,The residue was purified by chromatography (SiO₂, 1% CH₃OH—CH₂Cl₂) toafford the desired Boc-protected material (988 mg, 48%). The product wastreated with 3 M HCl—CH₃OH (26 mL) and stirred at 25° C. for 1 h. Thesolvent was removed in vacuo and the residue was dissolved in^(t)BuOH-H₂O (26 mL). Dowex 500 anion exchange resin was added untilpH=9. The resin was filtered and solution concetrated to afforded thedesired product (702 mg, 98%).

General Alkylation of 1-(3,3-Diphenylpropyl)piperazine

1-(3,3-Diphenylpropyl)piperazine (50 mg, 0.178 mmol) was dissolved inCH₃CN (1 mL) and was treated with alkylating agent (0.196 mmol, 1.1equiv) and ¹PrNEt 40 μL, 0.232 mmol, 1.3 equiv). The reaction mixturewas heated to 70° C. for 16 h. The solvent was removed and the sampleswere purified by normal column chromatography or preparative RPLC.

Example 291

Compound No. 236 (di-TFA salt, 72 mg, 53%) was prepared from 1-(3,3-diphenylpropyl )piperazine (50 mg, 0.178 mmol) and Maybridge GK 02253(46 mg, 0.196 mmol) employing general alkylation procedure. RPLCt_(R)=2.12 min (>90%), 220 nm (Method A ); ESI/MS m/e 477.2 (M⁺+H,C₂₇H₃₂N₄O₂S).

Example 292

Compound No. 10 (di-TFA salt, 36 mg, 27%) was prepared from1-(3,3-diphenylpropyl )piperazine (50 mg, 0.178 mmol) andN-(phenacyl)chloroacetamide (42 mg, 0.196 mmol) employing generalalkylation procedure. RPLC t_(R)=2.41 min (>95%), 220 nm (Method A);ESI/MS m/e 456.5 (M⁺+H, C₂₉H₃₃N₃O₂).

Example 293

Compound No. 11 (di-TFA salt, 76 mg, 57%) was prepared from1-(3,3-diphenylpropyl )piperazine (50 mg, 0.178 mmol) and1-benzoyl-2-(chloroacetyl)hydrazine (42 mg, 0.196 mmol) employinggeneral alkylation procedure. RPLC t_(R)=2.26 min (>95%), 220 nm (MethodA); ESI/MS m/e 457.4 (M⁺+H, C₂₈H₃₂N₄O₂).

Example 294

Compound No. 12 (di-TFA salt, 54 mg, 46%) was prepared from1-(3,3-diphenylpropyl)piperazine (50 mg, 0.178 mmol) and2-hydroxy-5-nitrobenzyl bromide (46 mg, 0.196 mmol) employing generalalkylation procedure. RPLC t_(R)=2.20 min (>95%), 220 nm (Method A);ESI/MS m/e 432.2 (M⁺+H, C₂₆H₂₉N₃O₃).

Example 295

Compound No. 13 (43 mg, 49%) was prepared from1-(3,3-diphenylpropyl)piperazine (50 mg, 0.178 mmol) andN-(4-methoxy-2-nitrophenyl)-2-bromoacetamide (46 mg, 0.196 mmol)employing general alkylation procedure. RPLC t_(R)=2.66 min (>95%), 220nm (Method A); ESI/MS m/e 489.2 (M⁺+H, C₂₈H₃₂N₄O₄).

Example 296

Compound No. 14 (55 mg, 62%) was prepared from1-(3,3-diphenylpropyl)piperazine (50 mg, 0.178 mmol) andN-(4-acetamido-3-methoxyphenyl)-2-bromoacetamide (46 mg, 0.196 mmol)employing general alkylation procedure. RPLC t_(R)=2.27 min (>95%), 220nm (Method A); ESI/MS m/e 501.2 (M⁺+H, C₃₀H₃₆N₄O₃).

Example 297 Measurement of Inhibition of MIP-1α Binding to THP-1 Cellsby Test Compounds

Human monocytic leukemia cell line THP-1 was suspended in assay buffer(RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjustedto pH 7.4) to give a cell suspension of a concentration of 1×10⁷cells/mL. The test compound was diluted in the assay buffer and used asthe test compound solution. Iodinated human MIP-1α (DuPont NEN Co.) wasdiluted in assay buffer to 250 nCi/mL and used as the ligand solution.In a 96 well filter plate (Millipore Co.), 25 μL of test compoundsolution. 25 μL of labeled ligand solution and 50 μL of cell suspensionwere aliquoted into each well in this order, stirred (total reactionvolume 100 μL), and incubated for one hour at 18° C.

After the reaction, the reaction solution was filtered, and the filterwas washed twice with 200 μL of cold PBS (200 μL of cold PBS was addedand then filtered). The filter was removed and placed in an RIA tube(Iuchi Seieido Co.) and the radioactivity retained by the cells on thefilter were measured using a gamma counter (Aloka Co.).

To calculate the ability of test compounds to inhibit binding of humanMIP-1α to THP-1 cells, non-specific binding determined by adding 100 ngof unlabeled human MIP-1α (Peprotech Co.) in place of the test compoundwas subtracted, while the counts with no test compound added was takenas 100%.

Inhibition (%)=(1−(A−B)/(C−B))×100

(A, counts with test compound added: B, counts with 100 ng of unlabeledhuman MIP-1α added: C, counts with [¹²⁵I]-labeled human MIP-1α added).

When inhibition by the cyclic diamine derivative of this invention wasmeasured, for example, the following compounds demonstrated >20%inhibitory activity at 100 μM. These compounds are compound Nos. 1, 2,3, 9, 34, 50, 52, 53, 54, 57, 59, 63, 64, 65, 66, 71, 75, 76, 78, 79,80, 81, 82, 106, 107, 108, 109, 111, 112, 123, 197, 204, 210, 211, 212,213, 215, 216, 218, 220, 221, 222, 223, 233, 246, 250, 252, 253, 258,264, 265, 269, 270, and 297.

Example 298 Measurement of Inhibition of MCP-1 Binding to TP-1 Cells

1. Construction of Recombinant Baculovirus Carrying the Human MCP-1 Gene

Based on the previously published human MCP-1 gene sequence (for exampleT. Yoshimura et al., Febs Letters, 1989, 244, 487-493), two syntheticDNA primers (5′-CACTCTAGACTCCAGCATGA-3′ and 5′-TAGCTGCAGATTCTTGGGTTG-3′)flanked by restriction enzyme sites were used to amplify a DNA fragmentfrom cDNA derived from human endothelial cells (purchased from KurabowCo.); the amplified fragment was cut with the restriction enzymes (PstIand XbaI), ligated into a transfer vector pVL1393 (Invitrogen Co.), andthe resulting vector was co-transfected along with infectiousbaculovirus into Sf-9 insect cells and the supernatant was plaqueassayed to yield human MCP-1 gene baculovirus recombinant.

2. Synthesis of [¹²⁵I]-labeled Human MCP-1 Expressed in Baculovirus

Using the method of K. Ishii et al. (Biochem Biophys ResearchCommunications 1995, 206, 955-961), 5×10⁶ Sf-6 insect cells was infectedwith 5×10⁷ PFU (plaque forming units) of the above human MCP-1recombinant baculovirus and cultured for 7 days in Ex-Cell 401 medium.The culture supernatant was affinity purified using a heparin Sepharosecolumn (Pharmacia Co.) and then further purified using reverse phaseHPLC (Vydac C18 column) to prepare purified human MCP-1. The purifiedhuman MCP-1 was protein labeled by Amersham Co. using the Bolton Huntermethod to yield [¹²⁵I]-labeled baculovirus expressed human MCP-1(specific activity 2000 Ci/mmol).

3. Measurement of Inhibition of Binding of [¹²⁵I]-labeled BaculovirusExpressed Human MCP-1 to THP-1 Cells

Human monocytic leukemia cell line THP-1 was suspended in assay buffer(RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjustedto pH 7.4) to give a cell suspension of a concentration of 1×10⁷cells/mL. The test compound was diluted in the assay buffer and used asthe test compound solution. [¹²⁵I]-labeled human MCP-1 described abovewas diluted in assay buffer to 1 mCi/mL and used as the labeled ligandsolution. In a 96 well filter plate (Millipore Co.), 25 μL of testcompound solution, 25 μL of labeled ligand solution and 50 μL of cellsuspension were aliquoted into each well in this order, stirred (totalreaction volume 100 μL), and incubated for one hour at 18° C.

After the reaction, the reaction solution was filtered, and the filterwas washed twice with 200 μL of cold PBS (200 μL of cold PBS was addedand then filtered). The filter was removed and placed in an RIA tube(Iuchi Seieido Co.,), and the radioactivity retained by the cells on thefilter were measured using a gamma counter (Aloka Co.).

To calculate the ability of test compound to inhibit binding of humanMCP-1 to THP-1 cells, non-specific binding determined by adding 100 ngof unlabeled human MCP-1 in place of the test compound was subtracted,while the counts with no test compound added was taken as 100%.

Inhibition (%)=(1−(A−B)/(C−B))×100

(A, counts with test compound added; B, counts with 100 ng of unlabeledhuman MIP-1α added; C, counts with [¹²⁵I]-labeled human MCP-1 added).

When inhibition by the cyclic diamine derivative of this invention wasmeasured, for example, the following compounds demonstrated >20%inhibitory activity at 100 μM. These compounds are compound Nos. 1, 2,3, 4, 9, 10, 11, 36, 50, 51, 52, 55, 56, 58, 59, 61, 63, 64, 65, 67, 68,69, 72, 73, 75, 76, 78, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 96, 98, 99, 100, 101, 103, 104, 106, 107, 108, 109, 114, 116, 117,119, 121, 122, 123, 124, 125, 126, 128, 129, 131, 132, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 145, 146, 147, 148, 149, 151,152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 185, 186, 187,188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 214, 215, 220, 221,222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236,246, 248, 249, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261,262, 263, 264, 265, 267, 269, 271, 272, 273, 274, 275, 276, 277, 278,279, 280, 281, 282, 284, 287, 288, 293, 294, 295, 296, 298, and 299.

Example 299 Measurement of Inhibition of Binding of [¹²⁵I]-labeled HumanMCP-1 to Cells Expressing the MCP-1 Receptor

1. Derivation of Cells Expressing the MCP-1 Receptor

cDNA fragment containing the MCP-1 receptor reported by S. Yamagami etal., Biochemical Biophysical Research Communications 1994, 202,1156-1162) was cloned into the expression plasmid pCEP4 (Invitrogen Co.)at the NotI site, and the plasmid obtained was transfected into thehuman kidney epithelial cell line 293-EBNA using the Lipofectaminereagent (Gibco-BRL Co.). The cells were cultured in the presence of theselective agent (Hygromycin), and a stably expressing transfectant linewas obtained. The express ion of the receptor was confirmed by bindingof [¹²⁵I]-labeled human MCP-1.

2. Measurement of Inhibition of Binding of [¹²⁵I]-labeled BaculovirusExpressed Human MCP-1 to the MCP-1 Receptor Expressing Cells

The MCP-1 receptor expressing cells on tissue culture dishes werescraped using a call scraper and suspended in assay buffer(D-MEM(Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjust ed topH 7.4) to give a cell suspension of a concentration of 6×10⁶ cellls/mL.The test compound was diluted in the assay buffer to concentrations of0.16, 0.8, 4.20, and 100 μM. The remainder of the procedure was asdescribed in Example 163.

When inhibition by the cyclic diamine derivative of this invention wasmeasured, compound No. 36 for example showed dose dependent inhibitionwith 50% inhibitory concentration (IC₅₀) of 17 μM.

Example 300 Measurement of Inhibition of Cell Chemotaxis

In order to determine the inhibition of call chemotaxis by the compoundsof this invention, we measured call chemotaxis caused by monocytechemotactic factor MCP-1 using the human monocytic leukemia cell lineTHP-1 as the chemotactic cell according to the method of Fall et al. (J.Immunol. Methods, 190, 33, 239-247). 2×10⁶ cells/mL of THP-1 cells(suspended in RPMI-1640 (Flow Laboratories Co.) +10% FCS) was placed inthe upper chamber (200 μL) of a 96 well micro-chemotaxis chamber(Neuroprobe, registered tradename), and human recombinant MCP-1 in asame solution (Peprotech Co.) at a final concentration of 20 ng/mL wasplaced in the lower chamber, with a polycarbonate filter (PVP-free,Neuroprobe; registered tradename) placed between the two chambers, Thesewere incubated at 37° C. for 2 hr in 5% CO₂.

The filter was removed, and the cells which had migrated to theunderside of the filter was fixed, stained using Diff Quick (KokusaiShiyaku Co.) and then quantitated using a plate reader (Molecular DeviceCo.) at a wavelength of 550 nm to determine the index of cell migrationas a mean of 3 wells, In addition. test compounds were placed in theupper chamber along with THP-1, and the inhibition of cell migration(inhibition IC₅₀ (μM)) was determined. Inhibition was defined as ((cellsmigration induced MCP-1 with no test compound in the upperchamber)−(cells migration with no MCP-1 added in the lowerchamber)=100%), and the concentration of the test compound which gave50% inhibition was designated IC₅₀.

When the inhibition of cyclic diamine derivatives of the presentinvention was measured, the 50% inhibition concentration (IC₅₀) forcompound No. 36 was 9 μM and for compound No. 240 was 30 μM.

Example 301 Inhibition of Delayed Type Hypersensitivity Reaction in theMouse DNFB Induced Contact Hypersensitivity Model

7 week old male Balb/c mice (Charles River Co.) were maintained for 1week, after which the hair was shaved with an electric razor from theabdomen to the chest. 1 day and 2 days later, the shaved areas werepainted twice with 25 μL of 0.5% dinitrofluorobenzene (DNFB) (Wako PureChemicals Co.) in acetone:olive oil=4:1. At day 6, both side of theright ear was painted for an induction with 10 μL of 0.2%dinitrofluorobenzene (DNFB) (Wako Pure Chemicals Co.) in acetone:oliveoil=4:1, while the left ear was painted with 10 μL of acetone:oliveoil=4:l not containing DNFB. As a test agent, compound No. 36 orcompound No. 240 was dissolved in acetone to 20 mg/mL, and applied twiceat 30 min before and after the DNFB induction (25 μL/ear/dose).

In the control group (no drug administration group), the acetonesolution not containing any test compound was applied. There were 8 miceper group in both the control group and the experimental group. In orderto prevent licking off of the DNFB and test compound, the necklace formice were used during the study (Natsume Seisakujo Co.). At 48 hr afterDNFB induction, ear lobes were sampled using a spring loaded micrometer(Ozaki Seisakujo Co.). The change in the ear lobe thickness wascalculated according to the following formula.

Increase=100×((right ear lobe thickness after sensitization−right earlobe thickness prior to sensitization)/right ear lobe thickness prior tosensitization−(left ear lobe thickness after sensitization−left ear lobethickness prior to sensitization)/left ear lobe thickness prior tosensitization)

After exanguination, the isolated ear was fixed in formalin, andhematoxylin-eosin stained histopathological sections were prepared forimage analysis. Using a digital camera (Fuji Color Service, HC-1000)installed an an upright microscope and a personal computer-(Macintosh8100/100AV, using Photoshop software), the color images were digitized,and analyzed using a second image analysis software (NIH Image). Theparameters measured were epidermal thickening, edema (area of dermal andsubcutaneous tissues), and cellular infiltration of tissue (number ofnuclei in the dermis and subcutaneous tissues).

Both compounds showed significant inhibitory activity.

What is claimed is:
 1. A cyclic diamine selected from the groupconsisting of a compound of the formula (I) below:

and a pharmaceutically acceptable acid addition salt thereof wherein R¹and R² are the same or different from each other and are phenyl group oraromatic heterocyclic group having 1-3 heteratoms, selected from oxygenatoms, sulfur atoms, nitrogen atoms or combinations thereof, in whichthe phenyl or aromatic heterocyclic group is optionally substituted byone or more halogen atoms, hydroxy groups, C₁-C₈ lower alkyl groups,C₁-C₆ lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups,methylenedioxy groups, C₁-C₆ hydroxyalkyl groups, carboxy groups, C₂-C₇alkoxycarbonyl groups, C₂-C₇ alkanoyl amino groups, dioxolanyl groups,or by group represented by the formula: —NR⁵R⁶, or is condensed with abenzene ring to form a condensed ring, wherein the substituents for thephenyl or aromatic heterocyclic group and the condensed ring condensedwith a benzene ring are optionally substituted by any substituentsindependently selected from halogen atoms, hydroxy groups, or C₁-C₆lower alkoxy groups, and R⁵ and R⁶ are the same or different from eachother and are hydrogen atoms, C₁-C₆ lower alkyl groups, or C₂-C₆ loweralkenyl groups; R³ represents a hydrogen atom, hydroxy group, cyanogroup, C₁-C₆ lower alkoxy group or C₂-C₇ lower alkanoyloxy group, jrepresents an integer of 0-3; k is 3; R⁴ is a group represented by:—A¹—R⁷  1) wherein R⁷ is a phenyl group which is optionally substitutedwith one or more groups which are the same or different and are halogenatoms, hydroxy groups, amino groups, C₁-C₆ lower alkyl groups, C₁-C₆lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups,C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyl groups, C₁-C₆ alkylsulfonylgroups, trifluoromethylsulfonyl groups, (unsubstituted) phenylsulfonylgroups optionally substituted with a hydroxy group, 1-pyrrolylsulfonylgroups, C₁-C₆ hydroxyalkylsulfonyl groups, C₁-C₆ alkanoylamino groups,or a group represented by formula: —CONR⁸R⁹ in which R⁸ and R⁹, are thesame or different from each other, and are hydrogen atoms or C₁-C₆ loweralkyl groups; A¹ is a group represented by the formula: —(CH₂)_(m)— or agroup represented by formula: —(CH₂)_(p)—G—(CH₂)_(q)— in which Grepresents G¹ or G² wherein G¹ represents —O—, —CO—, —SO₂—, —CO—O—,—CONH—, —NHCO—, —NHCONH—, or —NH-SO₂—, and G² is —(C═NH)NH—SO₂—,—CO—NH—NH—CO—, —CO—NH—NH—CO—NR¹⁰—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, or—CO—N(CH₂—CO—OCH₃)—NH—CO—, R¹⁰ is a hydrogen atom or a phenyl group; mis an integer of 0-3; p is an integer of 1-3; and q represents 0 or 1;—A²—R¹¹  2) wherein A² is —CO— or —SO₂—; R¹¹ is: a) a phenyl groupoptionally substituted with one or more groups which are the same ordifferent and are halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ loweralkoxy groups, groups represented by formula —CH₂—NR¹²R¹³ or groupsrepresented by the formula:

b) an aromatic monocyclic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinationsthereof, optionally substituted with one or more groups which are thesame or different and are halogen atoms, C₁-C₆ lower alkyl groups, orC₁-C₆ lower alkoxy groups, or c) a group of the formula: —CH₂—NR¹⁵R¹⁶where R¹², R¹³, R¹⁴ and R¹⁵ are the same or different groups, and arehydrogen atoms, or C₁-C₆ lower alkyl groups and R¹⁶ is a phenyl group ora phenylalkyl group optionally substituted with one or more of the sameor different groups and are halogen atoms, C₁-C₆ lower alkyl group, orC₁-C₆ lower alkoxy group; —(CH₂)_(n)—R¹⁷  3) wherein n is an integer of1-4; and R¹⁷ represents a hydrogen atom, cyano group, C₂-C₇alkoxycarbonyl group, C₁-C₆ hydroxyalkyl group, C₂-C₆ lower alkynylgroup, C₃-C₆ cycloalkyl group, C₃-C₇ alkenoyl group, a group representedby the formula: —(CHOH)CH₂OR¹⁸, a group represented by the formula:—CO—NH—NH—CO—OR¹⁹, a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

in which n is an integer of 1-4; R¹⁸ is a C₁-C₆ lower alkyl group, C₂-C₆lower alkenyl group, or C₂-C₆ lower alkynyl group and R¹⁹ is a C₁-C₆lower alkyl group; wherein R¹⁷ is a group which, where applicable, isoptionally substituted at any possible sites by one or more of the sameor different groups, said substituents selected from halogen atoms,hydroxy groups, C₁-C₆ lower alkoxy groups, or C₁C₆ lower alkoxy groups, —(CH₂)_(r)—A³—R²⁰  4) wherein r represents an integer of 0-3; A³represents a single bond, —CO—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NH—,—CO—NH—CH₂—CO—, —CO—NH—NH-SO₂—, —(CHOH)—CH₂—, or —(CHOH)—CH₂OCH₂—; R²⁰represents an aromatic heterocyclic group containing 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinationsthereof in which the aromatic heterocyclic group is optionallysubstituted with one or more groups which are the same or different andare halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups,or pyrrolyl groups or is condensed with a benzene ring to form acondensed ring; or —CH₂—CO—NR²¹R²²  5) wherein R²¹ is a hydrogen atom ora C₁-C₆ lower alkyl group; R²² represents a hydrogen atom, C₁-C₆ loweralkyl group, or a group represented by the formula:

a group represented by the formula:

or R²¹ and R²² taken together with the nitrogen to which they areattached form a 4 to 7-membered saturated heterocycle, which may containan oxygen atom, sulfur atom, or another nitrogen atom; where srepresents 0 or 1; t represents an integer of 0-2; R²³ represents ahydrogen atom, hydroxy group, phenyl group, C₁-C₆ lower alkyl group, orC₁-C₆ lower alkoxy group; R²⁴ represents a hydrogen atom or phenyl groupwhich is optionally substituted with a hydroxy group; R²⁵ represents ahydrogen atom, phenyl group which may be substituted by a hydroxy group,C₂-C₇ alkoxycarbonyl group, C₁-C₆ lower alkyl group, C₁-C₆ alkylthiogroup, or 3-indolyl group; and R²⁶ represents a hydroxy group, aminogroup, C₁-C₆ lower alkoxy group, or phenylalkyloxy group; with theproviso that when R³ is a hydrogen atom, then j is not 0; that when R³is a hydrogen atom, a substituent for R⁷ is not a hydroxy, C₁-C₆ loweralkyl, nor C₁-C₆ lower alkoxy group; that when R³ is a hydrogen atom, G¹is not —O— nor —CO—; that when R³ is a hydrogen atom and R¹¹ is a phenylgroup, the substituent for R¹¹ is not a C₁-C₆ lower alkyl group; thatwhen R³ is a hydrogen atom, R¹⁷ is not a hydrogen atom, C₂-C₇alkoxycarbonyl group, nor C₁-C₆ hydroxyalkyl group; that when R³ is ahydrogen atom, r is not 0; that when R³ is a hydrogen atom, A³is not asingle bond or —CO—; that when R³ is a cyano group, then R⁷ is notunsubstituted; that when R³ is a cyano group, a substituent for R⁷ isnot a halogen atom, C₁-C₆ lower alkyl group, nor C₁-C₆ lower alkoxygroup; that when R³ is a hydrogen atom and j is not 0, then R⁷ is not a2-methoxyphenyl group and R⁴ is not a —CH₂—CONH—R⁷ nor (CH₂)—CO—R²⁰; andthat when R³ is a cyano group or hydroxy group, then R²⁰ is not apyridyl group.
 2. A cyclic diamine or its pharmacologically acceptableacid addition salt as set forth in claim 1, wherein j is 2 in formula(I).
 3. A cyclic diamine or its pharmacologically acceptable acidaddition salt as set forth in claim 1, wherein R³ is a hydrogen atom informula (I).
 4. A cyclic diamine or its pharmacologically acceptableacid addition salt as set forth in claim 1, wherein R³ is a hydroxylgroup in formula (I).
 5. A cyclic diamine or its pharmacologicallyacceptable acid addition salt as set forth in claim 1, wherein R¹ and R²are the same or different from each other and are substituted orunsubstituted phenyl group in formula (I).
 6. A cyclic diamine or itspharmacologically acceptable acid addition salt as set forth in claim 1,wherein R⁴ in formula (I) is a group of the formula —CH₂—R⁷ wherein R⁷is as defined for R⁷ in formula (I).
 7. A cyclic diamine or itspharmacologically acceptable acid addition salt as set forth in claim 1,wherein R⁴ is —CH₂—CO—NH—NH—CO—R⁷, —CH₂—CO—NH—NH—CO—CH₂—R⁷,—CH₂—CO—NH—NH—CO—NH—R⁷, —CH₂—CO—NH—CH₂—CO—R⁷, —CH₂—CO—NR—NH—CO—R²⁰,—CH₂—CO—NH—NH—CO—NH—R²⁰ or —CH₂—CO—NH—CH₂—CO—R²⁰ wherein R⁷ and R²⁰ areas defined for R⁷ and R²⁰ in formula (I).
 8. A method for treatingdiseases such as atherosclerosis, rheumatoid arthritis, psoriasis,asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis,pulmonary fibrosis, or myocarditis in which leukocytes infiltrate intothe pathogenic by inhibiting the binding of chemokines to the receptorof a target cell and/or its action on a target cell using apharmaceutical preparation containing as an effective ingredient, acyclic diamine, or its pharmacologically acceptable acid addition salt,represented by the formula (II) below:

wherein R¹ and R² are the same or different from each other and are aphenyl group or an aromatic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinationsthereof, in which the phenyl or aromatic heterocyclic group isoptionally substituted by one or more halogen atoms, hydroxy groups,C₁-C₈ lower alkyl groups, C₁-C₆ lower alkoxy groups, phenyl groups,benzyl groups, phenoxy groups, methylenedioxy groups, C₁-C₆ hydroxyalkylgroups, carboxy groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoylaminogroups, dioxolanyl groups, or by group represented by the formula:—NR⁵R⁶ or is condensed with a benzene ring to form a condensed ring,wherein the substituents for the phenyl or aromatic heterocyclic groupand the condensed ring condensed with a benzene ring are optionallysubstituted by any substituents independently selected from the groupconsisting of halogen atoms, hydroxy groups, and C₁-C₆ lower alkoxygroups, and R⁵ and R⁶ are the same or different from each other and arehydrogen atoms, C₁-C₆ lower alkyl groups, or C₂-C₆ lower alkenyl groups;R³ is a hydrogen atom, hydroxy group, cyano group, C₁-C₆ lower alkoxygroup or C₂-C₇ lower alkanoyloxy group; j represents an integer of 0-3;k represents 3; R⁴ is a group represented by: —A¹—R⁷  1) wherein R⁷ is aphenyl group which is optionally substituted by one or more groups whichare the same or different and are halogen atoms, hydroxy groups, aminogroups, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups, cyanogroups, nitro groups, triflouromethyl groups, C₂-C₇ alkoxycarbonylgroups, C₂-C₇ alkanoyl groups, C₁-C₆ alkylsulfonyl groups,triflouromethylsulfonyl groups, unsubstituted phenylsulfonyl groups orphenylsulfonyl groups optionally substituted with a hydroxy group,1-pyrrolylsulfonyl groups, C₁-C₆ hydroxyalkylsulfonyl groups, C₁-C₆alkanoylamino groups, or a group of the formula: —CONR⁸R⁹ in which R⁸and R⁹ are the same or different from each other, and are hydrogen atomsor C₁-C₆ lower alkyl groups; A¹ is a group of the formula: —(CH₂)_(m)—or a group represented by formula: —(CH₂)_(p)—G—(CH₂)_(q)— in which G isG¹ or G²; wherein G¹ represents —O—, —CO—, —SO₂—, —CO—O—, —CONH—,—NHCO—, —NHCONH—, or —NH—SO₂—; and G² represents —(C═NH)NH—SO₂—,—CO—NH—NH—CO—, —CO—NH—NH—CO—NR¹⁰—, —CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, or—CO—N(CH₂—CO—OCH₃)—NH—CO—; R¹⁰ is a hydrogen atom or a phenyl group; mis an integer of 0-3; p is an integer of 1-3; q represents 0 or 1;—A²—R¹¹  2) wherein A² is —CO— or —SO₂—; R¹¹ is; a) a phenyl group whichis optionally substituted by one or more groups which are the same ordifferent and are halogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ loweralkoxy groups, groups represented by formula —CH₂—NR¹²R¹³ or groupsrepresented by the formula:

b) an aromatic monocyclic heterocyclic group having 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinationsthereof, which is optionally substituted with one or more of the same ordifferent groups which are halogen atoms, C₁-C₆ lower alkyl groups, orC₁-C₆ lower alkoxy groups, or c) a group represented by the formula:—CH₂—NR¹⁵R¹⁶, where R¹², R¹³, R¹⁴ and R¹⁵, are the same or differentgroups, and are hydrogen atoms or C₁-C₆ lower alkyl groups and R¹⁶ is aphenyl group or a phenylalkyl group, which is optionally substituted byone or more of the same or different groups which are halogen atoms,C₁-C₆ lower alkyl group, or C₁-C₆ lower alkoxy group; —(CH₂)_(n)—R¹⁷  3)wherein n is an integer of 1-4; and R¹⁷ is a hydrogen atom, cyano group,C₂-C₇ alkoxycarbonyl group, C₁-C₆ hydroxyalkyl group, C₂-C₆ loweralkynyl group, C₃ -C₆ cycloalkyl group, C₃-C₇ alkenoyl group, a grouprepresented by the formula: —(CHOH)CH₂OR¹⁸, a group represented by theformula: —CO—NH—NH—CO—OR¹⁹, a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula:

a group represented by the formula

a group represented by the formula

a group represented by the formula

a group represented by the formula

in which n is an integer of 1-4; R¹⁸ is C₁-C₆ lower alkyl group, C₂-C₆lower alkenyl group, or C₂-C₆ lower alkynyl group and R¹⁹ represents aC₁-C₆ lower alkyl group; wherein R¹⁷ is a group which, where applicable,is optionally substituted at any possible sites by one or more of thesame or different groups, said substituents selected from halogen atoms,hydroxy groups, C₁-C₆ lower alkyl groups, or C₁-C₆ lower alkoxy groups,—(CH₂)_(r)A³—R²⁰  4) wherein r represents an integer of 0-3; A³represents a single bond, —CO—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NH—,—CO—NH—CH₂—CO—, —CO—NH—NH—SO₂—, —(CHOH)—CH₂—, or —(CHOH)—CH₂OCH₂—; R²⁰represents an aromatic heterocyclic group containing 1-3 heteroatoms,selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinationsthereof in which the aromatic heterocyclic group is optionallysubstituted by one or more of the same or different groups which arehalogen atoms, C₁-C₆ lower alkyl groups, C₁-C₆ lower alkoxy groups, orpyrrolyl groups or is condensed with a benzene ring to form a condensedring; —CH₂—CO—NR²¹R²²  5) wherein R²¹ is a hydrogen atom or C₁-C₆ loweralkyl group; R²² represents a hydrogen atom, C₁-C₆ lower alkyl group, ora group represented by the formula

a group represented by the formula

or R²¹ and R²² taken together with the nitrogen to which they areattached form a 4 to 7-membered saturated heterocycle, which may containan oxygen atom, sulfur atom, or another nitrogen atom; where srepresents 0 to 1; t represents an integer of 0-2; R²³ represents ahydrogen atom, hydroxy group, phenyl group, C₁-C₆ lower alkyl group, orC₁-C₆ lower alkoxy group; R²⁴ represents a hydrogen atom or phenyl groupwhich is optionally substituted with a hydroxy group; R²⁵ represents ahydrogen atom, phenyl group which may be substituted by a hydroxy group,C₂-C₇ alkoxycarbonyl group, C₁-C₆ lower alkyl group, C₁-C₆ alkylthiogroup, or 3-indolyl group; and R²⁶ represents a hydroxy group, aminogroup, C₁-C₆ lower alkoxy group, or phenylalkyloxy group; or a hydrogenatom, C₁-C₆ alkanoyl group, or C₂-C₇ alkoxycarbonyl group.  6)
 9. Amethod according to claim 8, wherein j is 2 in said formula (II) or itspharmacologically acceptable acid addition salt thereof.
 10. A methodaccording to claim 8, in which R³ is a hydrogen atom in said formula(II) or its pharmacologically acceptable acid addition salt thereof. 11.A method according to claim 8, in which R³ is a hydroxyl group in saidformula (II) or its pharmacologically acceptable acid addition saltthereof.
 12. A method according to claim 8, in which R¹ and R² are thesame or different from each other and are substituted or unsubstitutedphenyl group in said formula (II) or its pharmacologically acceptableacid addition salt thereof.
 13. A method according to claim 8, in whichR⁴ is a group of the formula: —CH₂—R⁷ wherein R⁷ is as defined for R⁷ insaid formula (II), or its pharmacologically acceptable acid additionsalt thereof.
 14. A method according to claim 8, in which R⁴ is a groupof the formula: —CH₂—R²⁰ wherein R²⁰ is as defined for R²⁰ in saidformula (II), or its pharmacologically acceptable acid addition saltthereof.
 15. A method according to claim 8, wherein R⁴ is—CH₂—CO—NH—NH—CO—R⁷, —CH₂—CO—NH—NH—CO—CH₂—R⁷, —CH₂—CO—NH—NH—CO—NH—R⁷,—CH₂—CO—NH—CH₂—CO—R⁷, —CH₂—CO—NH—NH—CO—R²⁰, —CH₂—CO—NH—NH—CO—NH—R²⁰ or—CH₂—CO—NH—CH₂—CO—R²⁰ wherein R⁷ and R²⁰ are as defined for R⁷ and R²⁰in said formula (II), or its pharmacologically acceptable acid additionsalt thereof.
 16. A method according to claim 8, wherein the chemokineis MIP-1a.
 17. A method according to claim 8, wherein the chemokine isMCP-1.
 18. A method according to claim 8, wherein the chemokine is IL-8.